Methods for the Treatment of Substance Abuse and Dependence

ABSTRACT

The present invention relates to methods of and compositions for treating and relieving symptoms and disease associated with indications caused by a physiological drive to alleviate a sensation of anxiety. More specifically, the present invention relates to methods of and compositions for treating and relieving symptoms associated with substance abuse and withdrawal. The present invention relates to methods of and compositions for treating and relieving symptoms associated with addiction to antidepressants, opiates, nicotine or marijuana. In one method, a patient is treated with a composition that directly or indirectly modulates GABA A  by modulating the expression of the GABA A  receptor a 4  subunit.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention relies on, for priority, U.S. Provisional PatentApplication No. 60/669,033, entitled “Improved Method for the Treatmentof Substance Abuse”, filed on Apr. 7, 2005, U.S. Provisional PatentApplication No. 60/728,979 entitled “Methods for the Treatment ofSubstance Abuse and Dependence”, filed on Oct. 21, 2005, and U.S.Provisional Patent Application No. 60/729,013 entitled “Methods forTreating Anxiety-Related Diseases”, filed on Oct. 21, 2005.

FIELD OF THE INVENTION

The present invention relates to methods of and compositions fortreating and relieving symptoms and disease associated with indicationscaused by a physiological drive to alleviate a sensation of anxiety.More specifically, the present invention relates to methods of andcompositions for treating and relieving symptoms associated withsubstance abuse and withdrawal. The present invention relates to methodsof and compositions for treating addiction to antidepressants, opiates,nicotine or marijuana.

The present invention is also relates to a methodology for diagnosing aperson in an altered GABA_(A) receptor state. In particular, themethodology is directed toward determining the relative receptivity of apatient to the treatment methodologies of the present invention byqualitatively or quantitatively measuring progesterone levels in apatient, or, more preferably, the allopregnanolone levels within apatient's brain.

The present invention also relates to a treatment methodology that, in afirst stage, improves a patient's physiological receptivity totreatment. In particular, the methodology is directed toward preventingthe up-regulation of endogenous neuroactive steroids or activelydown-regulating the production of endogenous neuroactive steroids toavoid cross-tolerance effects between exogenous and endogenoussubstances.

The present invention also relates to a treatment methodology that, in asecond stage, employs methods of and compositions for modulating theexpression of certain GABA_(A) receptor subunits, thus treating thewithdrawal symptoms associated with psychological and physiologicaladdiction and dependence in a comprehensive treatment plan. The presentinvention also relates to optionally employing conventional treatmentprograms in combination with the methods of and compositions of thepresent invention in a comprehensive treatment plan.

More specifically, the present invention relates to methods of, devicesfor, and treatment protocols for using pharmaceutical compositions froma class of compounds that directly or indirectly modulates GABA_(A) bymodulating the expression of the GABA_(A) receptor α₄ subunit.

The present invention also relates to a class of compounds, and methodsof identifying such compounds, that modulates the expression of certainGABA_(A) receptor subunits. More specifically, the compound of choice isone that a) acts as a partial agonist of GABA_(A); b) inhibits theupregulation of the GABA_(A) receptor 4 subunit and/or increases therelative ratio of the GABA_(A) receptor α₁ subunit to the GABA_(A)receptor α₄ subunit; and c) does not cause the upregulation of theGABA_(A) receptor α₄ subunit and/or does not cause the decrease of therelative ratio of the GABA_(A) receptor α₁ subunit to the GABA_(A)receptor α₄ subunit once the composition is no longer present in thepatient's system.

BACKGROUND OF THE INVENTION

Substance addiction and abuse is a multi-factorial neurological disease.Over time, repeated exposure to various substances, both endogenous andexogenous, causes modification of the neurotransmission circuits andadaptations in post-receptor signaling cascades. There are severaleffects of this neuronal modification. Among them, there is a reductionin the ability of natural rewards to activate the reward pathwaysleading to depressed motivation and mood and an increased compulsion tocompensate for the physiological change.

While the common perception underlying addiction is that of a “rewardcircuit”, pleasure may not necessarily be a strong enough impetus todrive people towards their addictions. Rather, addictive behavior arisesfrom an intense desire to manage and/or avoid the anxiety that ariseswhen someone is experiencing withdrawal.

Traditional treatments for substance dependency, such as benzodiazepineabuse, have been based upon cognitive-behavioral therapy or drugtherapy, or a combination thereof. Conventional methods of treatmentfail, however, in that they do not address the physiochemical changesthat occur with addiction and dependence. Thus, conventional treatmentsfor controlling withdrawal symptoms and cravings for addictivesubstances have had limited success and often have undesirable sideeffects.

What is therefore needed are improved methods of, compositions for, andtreatment protocols for preventing psychological addiction to, andphysiological dependence upon addictive substances.

What is also needed is an improved treatment methodology for controllingcravings and withdrawal symptoms caused by substance abuse.

What is also needed is an improved methodology and protocol for treatingsubstance abuse, which results in reduced patient dropout rates.

SUMMARY OF THE INVENTION

According to its major aspects and broadly stated, the present inventionis directed towards methods of, and compositions for, preparing apatient for treatment and modulating the expression of certain GABA_(A)receptor subunits. The present invention therefore treats withdrawalsymptoms associated with psychological addiction and physiologicaldependence upon various exogenous and endogenous substances in thecontext of a comprehensive treatment plan of behavioral and/orpharmacological treatment.

The multiple phase treatment methodology of the present inventionemploys one or more compounds to reset physiochemical changes in apatient that is experiencing withdrawal from addictive and/ordependency-inducing substances, including but not limited to opioids andderivatives, nicotine, benzodiazepines, caffeine, cannabis, oranti-depressant drugs.

The present invention relates to methods of and compositions fortreating and relieving symptoms and disease associated with indicationscaused by a physiological drive to alleviate a sensation of anxiety.More specifically, the present invention relates to methods of andcompositions for treating and relieving symptoms associated withsubstance abuse and withdrawal. In one embodiment, a patient is treatedwith a composition from a class of compounds that directly or indirectlymodulates GABA_(A) by modulating the expression of the GABA_(A) receptorα₄ subunit.

The present invention also provides methods that, in a first stage,improve an individual's physiological receptivity to treatment. Inparticular, the methodology is directed toward preventing theup-regulation of endogenous neuroactive steroids or activelydown-regulating the production of endogenous neuroactive steroids toavoid cross-tolerance.

The present invention also provides methods that, in a second stage,employs methods of, and compositions for, modulating the expression ofcertain GABA_(A) receptor subunits, thus treating the withdrawalsymptoms associated with psychological and physiological addiction anddependence in a comprehensive treatment plan. The present invention alsorelates to optionally employing conventional treatment programs incombination with the methods of and compositions of the presentinvention in a comprehensive treatment plan.

Methods are also provided for treating anti-depressant addiction byadministering a compound from a class of compounds that selectivelymodulates GABA_(A) receptor expression. In one embodiment, the methodincludes the steps of assessing a patient for treatment compatibility;preparing a patient for treatment; and administering a compound from theclass of compounds that selectively modulates GABA_(A) receptorexpression to a patient.

Methods are also provided for treating opiate addiction comprising thestep of administering a compound from a class of compounds thatselectively modulates GABA_(A) receptor expression. In one embodiment,the method includes the steps of assessing a patient for treatmentcompatibility; preparing a patient for treatment; and administering acompound from the class of compounds that selectively modulates GABA_(A)receptor expression to a patient.

Methods are also provided for treating nicotine addiction where themethod includes the steps of assessing a patient for treatmentcompatibility; preparing a patient for treatment; and administering acompound from the class of compounds that selectively modulates GABA_(A)receptor expression to a patient.

Methods are also provided for treating marijuana addiction where themethod includes the steps of assessing a patient for treatmentcompatibility; preparing a patient for treatment; and administering acompound from the class of compounds that selectively modulates GABA_(A)receptor expression to the patient.

The present invention also provides a class of compounds, and methods ofidentifying such compounds, that modulates the expression of certainGABA_(A) receptor subunits. More specifically, the compound of choice isone that a) acts as a partial agonist of GABA_(A); b) inhibits theupregulation of the GABA_(A) receptor α₄ subunit and/or increases therelative ratio of the GABA_(A) receptor α₁ subunit to the GABA_(A)receptor α₄ subunit; and c) does not cause the upregulation of theGABA_(A) receptor α₄ subunit and/or does not cause the decrease of therelative ratio of the GABA_(A) receptor α₁ subunit to the GABA_(A)receptor α₄ subunit once the composition is no longer present in thepatient's system.

It is therefore an object of the invention to provide methods andcompositions for inhibiting the formation of neurosteriods.

It is another object of the invention to provide methods andcompositions for modulating chloride channels such as GABA_(A)receptors.

It is another object of the invention to provide methods andcompositions for treating symptoms of stimulant substance abuse.

It is another object of the invention to provide methods andcompositions for treating addiction to antidepressants, opiates,nicotine or marijuana.

Another object of the invention is to provide for the use of a GABA_(A)receptor modulator in the preparation of a medicament to treat addictionto antidepressants, opiates, nicotine or marijuana.

Another object of the invention is to provide for the use of aneurosteroid production inhibitor in the preparation of a medicament totreat addiction to antidepressants, opiates, nicotine or marijuana.

These and other objects, features and advantages of the presentinvention will become apparent after a review of the following detaileddescription of the disclosed embodiments and claims and the drawingsprovided.

BRIEF DESCRIPTION OF THE DRAWINGS

The Detailed Description should be considered in light of the drawings,as briefly described below:

FIG. 1 illustrates the spectrum between inhibition and substantially orcompletely reduced inhibition via the direct and/or indirect allostericmodulation of GABA_(A);

FIG. 2 illustrates the internal thought filtering mechanism in aperson's brain;

FIG. 3 a is a first schematic presentation of a plurality of GABA_(A)receptor subunits;

FIG. 3 b is a second schematic presentation of a plurality of GABA_(A)receptor subunits;

FIG. 3 c is an illustration of the insensitivity of the modulatedGABA_(A) receptor to benzodiazepines. Note the α1 subunit:α1β2γ2-containing GABA_(A) receptors are the most common GABA receptorsin the brain.

FIG. 4 is a chemical diagram of the blockade of the conversion ofprogesterone to allopregnanolone via inhibitors of neurosteroidproduction.

DETAILED DESCRIPTION OF THE INVENTION I. Introduction

Drug addiction is a disorder characterized by compulsive drug intake,loss of control over intake, and impairment in social and occupationalfunction. Allostatic changes in reward function lead to excessive drugintake, providing a framework with which to identify the neurobiologicmechanisms involved in the development of drug addiction.Neuropharmacologic studies have provided evidence for the dysregulationof specific neurochemical mechanisms in brain reward and stress circuitsthat result in negative reinforcement or essentially, decreased efficacyof brain reward pathways, further resulting in addiction. The allostaticmodel integrates molecular, cellular and circuitry neuroadaptations inbrain motivational systems produced by chronic drug ingestion withgenetic vulnerability. Both positive and negative changes in mood arestrongly correlated with allostasis in substance dependence. Inaddition, it has been shown that substance abuse leads to prolongedalterations in neurophysiological responses to corticotrophin-releasingfactor (CRF) and neuropeptide Y (NPY), peptides known to influencestress responses.

Substance abuse, however, may be more accurately characterized asdisease further characterized by an individual's need to avoid adverseeffects. In a typical dependence and subsequent withdrawal situation,repeated exposure to drugs causes neurological dysfunction which sets inmotion a cascade of changes by which motivation and drive (via theanterior cingulate), reward (via the nucleus accumbens and ventraltegmental area), and memory and learning functions (via the amygdala andhippocampus) are modified, resulting in the loss of cortical inhibitoryinfluence (orbitofrontal cortex, where control is located). This loss ofinhibitory control contributes to craving and irrational behavior toobtain and consume drug regardless of consequences, despite the factthat, in many cases, the reward center is decreasingly responsive.

The GABAergic system, responsible for most inhibitory control, typicallybegins with the GABA_(A) receptor and glutamate receptors in allostaticequilibrium. Allostatic equilibrium refers to the normal complement ofreceptors on the cell membrane in a normal individual not experiencingdependency, tolerance, or withdrawal. Intake of a particular substanceleads to feeling of reward and reduced anxiety in a subject. The“substance” is defined as any substance that will relieve anxiety.Long-term use and subsequent withdrawal from a substance, however,causes GABA dysregulation mediated through GABA_(A) receptors, causingthe glutamate and GABA_(A) receptors to lose their relative allostaticequilibrium, further resulting in modified levels of inhibition.

Thus, when the GABA_(A) receptor is dysregulated, the clinicalmanifestation of this dysregulation is initially anxiety. In addition,the anxiety is often accompanied by compulsive behavior. Certaincompulsive behaviors, such as but not limited to drug abuse, gambling,compulsive sexual activity, and compulsive video game playing, can leadto increased euphoria, neurosteroid production and brain simulation.Subsequent discontinuation of these activities can result in withdrawalsyndrome that manifests itself through heightened anxiety and GABA_(A)regulator dysregulation.

In a non-dependent subject, the most common GABA_(A) receptor in thebrain is the α₁β₂γ₂ receptor, which is a benzodiazepine sensitivereceptor. The α₁ subunit is an important binding site forbenzodiazepines. During a person's withdrawal from an addictivesubstance, the amount of α₁ subunits decreases relative to the amount ofα₄ subunits. Withdrawal from the substance often causes symptoms ofdepression, anxiety, impulsivity, and dysphoria, as GABA uptake isdecreased due to the reduced number of GABA_(A) receptor α₁ subunitsrelative to GABA_(A) receptor α₄ subunits. Benzodiazepines do not bindfavorably to the α₄ subunit, and, therefore, the α₄β₂γ₂ receptor isconsidered a benzodiazepine insensitive receptor. People who have a highamount of α₄ receptor subunits relative to α₁ receptor subunits can beconsidered to be in a “withdrawal state”. The present invention is thusdirected towards restoring an individual to a non-withdrawal state, or a“normal” receptor balance, from a “withdrawal state”.

The present invention is also directed towards methods of andcompositions for treating and relieving symptoms and disease associatedwith indications caused by a physiological drive to alleviate asensation of anxiety. The present invention is also directed towardsmethods of and compositions for treating and relieving symptomsassociated with substance abuse and withdrawal.

The present invention is further directed towards a class of compounds,and methods of identifying such compounds, that modulates the expressionof certain GABA_(A) receptor subunits. More specifically, the compoundof choice is one that a) acts a partial agonist of GABA_(A); b) inhibitsthe up-regulation of the GABA_(A) receptor α₄ subunit and/or increasesthe relative ratio of the GABA_(A) receptor α₁ subunit to the GABA_(A)receptor α₄ subunit; and c) does not cause the up-regulation of theGABA_(A) receptor α₄ subunit and/or does not cause the decrease of therelative ratio of the GABA_(A) receptor α₁ subunit to the GABA_(A)receptor α₄ subunit once the composition is no longer present in thepatient's system.

The present invention is also directed towards a methodology fordiagnosing a person in an altered GABA_(A) receptor state. Inparticular, the methodology is directed toward determining the relativereceptivity of a patient to the treatment methodologies of the presentinvention by measuring progesterone levels in a patient, or, morepreferably, the allopregnanolone levels within a patient's brain.

The present invention is also directed towards a treatment methodologythat, in a first stage, improves a patient's physiological receptivityto treatment. In particular, the methodology is directed towardpreventing the up-regulation of endogenous neuroactive steroids oractively down-regulating the production of endogenous neuroactivesteroids to avoid cross-tolerance.

The present invention is also directed towards a treatment methodologythat, in a second stage, employs methods of and compositions formodulating the expression of certain GABA_(A) receptor subunits incombination with conventional treatment programs, thus treating thewithdrawal symptoms associated with psychological and physiologicaladdiction and dependence in a comprehensive treatment plan.

More specifically, the present invention is directed towards methods of,devices for, and treatment protocols for using pharmaceuticalcompositions from a class of compounds that directly or indirectlymodulates GABA_(A) by modulating the expression of the GABA_(A) receptorα₄ subunit.

The present invention is further directed towards methods of, devicesfor, and treatment protocols for treating substance abuse, dependence,and tolerance.

II. The GABAergic System

a. Gamma-Aminobutyric Acid (GABA)

GABA is a neurotransmitter that acts at inhibitory synapses in the brainand spinal cord. The GABA system is found, among other places, in thehippocampus, an area of the brain associated with memory formation.Glutamic acid, or glutamate, is important in brain function, as anexcitatory neurotransmitter and as a precursor for the synthesis of GABAin GABAergic neurons. Glutamate activates both ionotropic andmetabotropic glutamate receptors, described in further detail below.GABA signals interfere with registration and consolidation stages ofmemory formation.

b. GABA Receptor Types

The GABA receptors are a group of receptors with GABA as theirendogenous ligand. Several classes of GABA receptors are known,including ionotropic receptors, which are ion channels themselves, andmetabotropic receptors, which are G-protein coupled receptors that openion channels via intermediaries. Glutamate and GABA mediate theiractions by the activation of their receptors.

The ionotropic GABA receptors (GABA_(A) receptors) are based on thepresence of eight subunit families consisting of 21 subunits (α₁₋₆,β₁₋₄, γ₁₋₄, δ, ε, π, θ, ρ₁₋₃) and display an extraordinarily structuralheterogeneity. GABA_(A) receptors are composed of five circularlyarranged, homologous subunits and are important sites of drug action.Most often, the GABA_(A) receptor isomers comprise two α subunits, two βsubunits and one γ subunit. The metabotropic GABA receptors (GABA_(B)receptors) consist of two subunits: GABA_(B1) and GABA_(B2).Physiological responses following activation of GABA_(B) receptorsrequire the co-assembly of GABA_(B1) and GABA_(B2). GABA_(C) receptorsalso exist natively.

c. GABA_(A) Receptor Subunits

The GABA_(A) receptor system is implicated in a number of centralnervous system disorders, making GABA_(A) receptor ligands potentialtherapeutic agents. GABA_(A) receptors are ligand-gated ion channelsthat belong to the same super family of receptors as glycine, nicotiniccholinergic, and serotonin 5HT₃ receptors. Enhanced function of severalGABA_(A) receptors accounts for the major actions of benzodiazepines,described in greater detail below. In addition, a number of compoundshave exhibited functional selectivity for GABA_(A) receptors.

The GABA_(A) receptor complex is a pentameric receptor protein structureformed by co-assembly of subunits from seven different classes. Fivesubunits are situated in a circular array surrounding a centralchloride-permeable pore. It has been suggested that the mechanism forligand-induced channel opening in nicotinic acetylcholine receptorsinvolves rotations of the subunits in the ligand binding domain.Assuming that GABA_(A) receptors utilize a similar mechanism for channelopening, since GABA_(A) receptors belong to the same super family as thenicotinic acetylcholine receptors, large substituents may interfere withthe channel opening (steric hindrance) resulting in antagonistic effectsof certain compounds. In addition, the activation of GABA receptors willinfluence several other systems, ultimately resulting in a general acutemodification of the overall function of the central nervous system.

The particular combination of subunits yields receptors with differentpharmacological and physiological properties, however, the GABA_(A)receptor composition is not immutable. Withdrawal from anxiolyticbenzodiazepines, which produce their effects by facilitating GABA_(A)receptor mediated inhibition, yields an increase in the steady statemRNA levels of α₄ and β₁ subunit mRNA in both the cortex andhippocampus. It should be noted that the δ subunit is often associatedwith GABA_(A) receptor subtypes containing the α₄ subunit.

GABA and GABA_(A) receptors are involved in disease states such asseizures, depression, anxiety and sleep disorders. GABA and some of theother indirectly or directly acting GABA_(A) receptor agonists(GABA-mimetics), including allopregnanolone andtetrahydrodeoxycorticosterone respectively, bind specifically to arecognition site located at the interface between an α and a β subunit.The classical benzodiazepines, however, such as diazepam andflunitrazepam, bind to an allosteric site located at the interfacebetween an α and a γ subunit.

More specifically, GABA binds to the cleft between α and β subunits, anaction which gates open the chloride channel to allow for the influx ofchloride ions into the cell. This typically hyperpolarizes the cell,having an inhibitory action on neuronal activity, by making the membranepotential of the cell more negative, and consequentially, increases thedepolarization threshold to generate an action potential.

Most depressant and sedative drugs such as the benzodiazepinetranquilizers, barbiturates, anesthetics and alcohol are believed have amodulatory effect on the GABA_(A) receptor at unique sites where theycan enhance the actions of GABA in accumulating negatively chargedchloride ions into the cell, inducing sedative or anesthetic effects.

The conformational restriction of various parts of the molecule of GABAand biosteric replacements of the functional groups of the amino acidleads to a broad spectrum of specific GABA_(A) agonists. Some of thesemolecules have played a key role in the understanding of thepharmacology of the GABA_(A) receptor family.

The absence or presence of a particular α subunit isoform in theGABA_(A) receptors confers selectivity for certain drugs. Different αsubunits also mediate distinct pharmacological actions ofbenzodiazepines, including sedative-hypnotic and anxiolytic effects.Long-term administration of benzodiazepines results in the developmentof tolerance to some of the effects of these drugs, thus reducing theirclinical efficacy. While the molecular basis for these dependenciesremains unclear, tolerance and dependence appear to be related to thepharmacodynamics of benzodiazepines.

Long-term administration of benzodiazepines modifies the expression ofgenes that encode various GABA_(A) subunits. These changes in geneexpression alter the sensitivity of GABA_(A) receptors to theirpharmacological modulators and thereby underlie the development oftolerance to or dependence on these drugs. The subunit composition ofGABA_(A) receptor determines their affinity for benzodiazepine receptorligands as well as the efficacy of these ligands. For example, classicalbenzodiazepine agonists (e.g. diazepam), imidazopyridines,imidazoquinolones and pyrazolopyrimidines show no affinity for orefficacy at GABA_(A) receptors that contain α₄ or α₆ subunits.

The subunit composition of native GABA_(A) receptors plays an importantrole in defining their physiological and pharmacological function. It ispossible to characterize the physiological, pharmacological, andpathological roles of GABA_(A) receptors by understanding the mechanismsby which the subunit composition of GABA_(A) receptors is regulated.Thus, the expression of specific GABA_(A) receptor subunit genes may beaffected by various physiological and pharmacological modulators,including but not limited to, pharmacological agents, endogenousneurosteroids, and food.

For example, long-term exposure to and subsequent withdrawal ofbenzodiazepines, zalpelon, zolpidem, or neurosteroids result inselective changes in the expression of specific GABA_(A) receptor mRNA,including an increase of the α₄ subunit mRNA, and polypeptide subunitsand in GABA_(A) receptor function in cultured cells. Withdrawal fromdiazepam or imidazenil was associated with both a reduced ability ofdiazepam to potentiate GABA action and the ability of flumazenil topotentiate GABA action. Chronic benzodiazepine treatment and subsequentwithdrawal lead to a change in the receptor subunit composition, andthese new synthesized receptors are less responsive to benzodiazepines.The up-regulation of the α₄ subunit, however, may be necessarily coupledwith the down-regulation of other subunits for the development ofbenzodiazepine dependence.

Withdrawal of zalpelon or zolpidem, like that of diazepam, induced amarked increase in the amount of α₄ subunit mRNA. These effects ofzalpelon and zolpidem on GABA_(A) receptor gene expression areconsistent with the reduced tolerance liability of these drugs, comparedwith that of diazepam, as well as with their ability to induce bothphysical dependence and withdrawal syndrome.

Ethanol withdrawal-induced increases in the amounts of α₄ subunit mRNAand protein are associated with reduced sensitivity of GABA_(A)receptors to GABA and benzodiazepines. The effects of alcohol aresimilar to those of drugs that enhance the function of GABA_(A)receptors, which gate the Cl-currents that mediate most inhibitoryneurotransmission in the brain, as described above. Acutely high dosesof alcohol potentiate GABA-gated currents at both native and recombinantGABA_(A) receptors, and chronically alter GABA_(A) receptor expression.Ethanol elicits its central effects through modulation ofneurotransmission mediated by various receptors, especially thatmediated by GABA_(A) receptors. It has been shown that long-term ethanoladministration also affects the subunit composition and, consequently,the functional properties of native GABA_(A) receptors. Thepharmacological profile of ethanol is similar to that of benzodiazepineand also results in the development of cross-tolerance and dependence.

Exposure to diazepam at the time of ethanol withdrawal antagonizes thewithdrawal-induced increase in the abundance of the α₄ subunit mRNA. Thereplacement of ethanol with diazepam also blocked the ethanolwithdrawal-induced impairment in cellular metabolism. Cells exposed toGHB at the time of ethanol withdrawal results in an inhibition in theincrease in the abundance of the α₄ subunit mRNA.

The modulatory action of flumazenil in cells that are exposed to ethanolis similar to that measured in cells not exposed to ethanol. Incontrast, however, in ethanol withdrawn cells, 3 μM flumazenilpotentiates the GABA evoked Cl-current consistent with the ethanolwithdrawal-induced up-regulation of the α₄ subunit in these cells. Thesubstitution of 10 μM diazepam or 100 mM GHB for ethanol negated thepositive modulation of 3 μM flumazenil induced by ethanol withdrawal.

The presence of the α₄ subunit in recombinant GABA_(A) receptors isassociated with a reduced sensitivity to classical benzodiazepineagonists and to zolpidem as well as with a distinct pattern ofregulation (positive rather than no allosteric modulation) byflumazenil.

In general, chronic treatment with agonists that act at different sitesof the GABA_(A) receptor results in changes in the biochemical andfunctional properties of the receptor that are accompanied by changes inthe abundance of specific receptor subunit mRNAs. In addition, chronictreatment with substances that modulate GABA_(A) function via aneurosteroid pathway results in changes in the biochemical andfunctional properties of the receptor that are accompanied by changes inthe abundance of specific receptor subunit mRNAs. The observation thatthe ethanol withdrawal-induced increase in the expression of the α₄subunit gene in cultured cerebellar granule cells is prevented bydiazepam is consistent with the fact that benzodiazepine treatments areeffective in treating alcohol withdrawal symptoms in humans. Thus, arapid and marked increase in the abundance of the α₄ subunit induced byethanol withdrawal might therefore contribute to the development ofdiazepam-sensitive withdrawal symptoms in humans.

III. GABA and Neurosteroids

Characterizations of the role of GABA_(A) receptors require anunderstanding of the mechanisms by which subunit composition isregulated. The long-term administration of sedative-hypnotic,anxiolytic, or anticonvulsant drugs can affect expression of GABA_(A)receptor subunit genes as well as the drug sensitivity and function ofthese receptors, suggesting that the mechanisms responsible for suchchanges might also underlie the physiological modulation of GABA_(A)receptors by endogenous compounds such as neurosteroids.

The neuroactive steroids 3α-hydroxy-5α-pregnan-20-one (allopregnanolone)and 3α,21-dihydroxy-5α-pregnan-20-one(allotetradihydrodeoxycorticosterone, or THDOC) induce anxiolytic,sedative, hypnotic, and anticonvulsant effects similar tobenzodiazepines and other anxiolytic drugs. The concentrations of theseneurosteroids are increased in the brain of humans both in response totreatment with anxiogenic, antidepressant or antipsychotic drugs as wellas physiological or pathological conditions (such as depression, stress,the luteal phase of the menstrual cycle, and pregnancy) that affect moodand emotional state. Additional studies implicate endogenousallopregnanolone as a physiological regulator of both basal andstress-induced dopamine release in the rat brain.

Steroid metabolites react with the GABA receptor complex to alter brainexcitability. Several of these steroids accumulate in the brain afterlocal synthesis or after metabolism of adrenal steroids. Neurosteroidsare synthesized in the peripheral and central nervous system, fromcholesterol or steroidal precursors imported from peripheral sources.Both progesterone and estrogen alter excitability of neurons of thecentral nervous system. For example, estrogen reduces inhibition at theGABA_(A) receptor, enhances excitation at the glutamate receptor, andincreases the number of excitatory neuronal synapses. In contrast,progesterone enhances GABA-mediated inhibition, increases GABAsynthesis, and increases the number of GABA_(A) receptors. Inparticular, progesterone and its metabolites have been demonstrated tohave profound effects on brain excitability. The levels of progesteroneand its metabolites vary with the phases of the menstrual cycle,decreasing prior to the onset of menses. Progesterone is readilyconverted to allopregnanolone (3α-OH-5α-pregnan-20-one or 3α,5α-THP) inhuman brains. Allopregnanolone-induced GABA_(A) receptor dysregulationhas been closely linked to major anxiety-related diseases, thus linkinganxiety to allopregnanolone “withdrawal”.

Neurosteroids rapidly alter neuronal excitability thorough interactionwith neurotransmitter-gated ion channels. Allopregnanolone is a positivepotent modulator of the GABA_(A) receptor and enhances the action whichgates open the chloride channel to allow influx of chloride ions intothe cell. This typically hyperpolarizes the cell, having an inhibitoryaction on neuronal activity, and thus allopregnanolone acts as asedative or anxiolytic agent and decreases anxiety.

GABA_(A)-modulatory allopregnanolone, as described above, is alsoresponsible for producing anxiogenic withdrawal symptoms. The withdrawalprofile shown therein is similar to that reported for otherGABA_(A)-modulatory drugs such as the benzodiazepines, barbiturates, andethanol. Thus, the actions of neuroactive steroids on traditionaltransmitter receptor in the brain lead to alterations in the GABA_(A)receptor subunit composition that result in changes in the intrinsicchannel properties of the receptor and behavioral excitability. Changesare also associated with significant increases in both the mRNA andprotein for the α₄ subunit of the GABA_(A) receptor in the hippocampus.It has also been demonstrated that chronic administration ofprogesterone inhibits the upregulation of the α₄ subunit of the GABA_(A)receptor and/or suppresses receptor activity.

Thus, the endogenous neurosteroid allopregnanolone exhibits withdrawalproperties, similar to GABA-modulators such as tranquilizers andalcohol, as described above, increasing anxiety susceptibility followingabrupt discontinuation after chronic administration. The increase inneuronal excitability has been attributed to upregulation of theGABA_(A) α₄ subunit. Thus, the α₄β₂γ is preferentially expressedfollowing hormone withdrawal. Blockade of the α₄ gene transcriptprevents withdrawal properties.

The increase in expression of the GABA_(A) receptor α₄ subunit relativeto the GABA_(A) receptor α₄ subunit can thus be attributed to manyfactors. These include, but are not limited to 1) compositions, bothendogenous and exogenous, which, upon withdrawal, increase the GABA_(A)receptor α₄ subunit relative to the GABA_(A) receptor α₁ subunit; and 2)compositions, both exogenous or endogenous that result in the increaseof expression of the GABA_(A) receptor α₄ subunit or the decrease ofexpression of the GABA_(A) receptor α₁ subunit.

Certain substances, both endogenous and exogenous, can causemodifications in the allostatic control of GABA_(A), directly orindirectly, via an endogenous neurosteroid pathway. Most substances thatcross the blood-brain barrier in sufficient quantity can stimulate aneuroprotective, neurosteroid response. In general, the moreneuroexcitatory the substance, the more neurosteroid response isachieved. With the up-regulation of neurosteroids, GABA_(A) receptoractivity is enhanced, causing a constant state of activation which, overtime, may cause neurosteroid tolerance. Therefore, once theneuroexcitatory substance is no longer present, the brain's neurosteroidlevels will decrease to natural levels, causing the individual to gothrough a state of “withdrawal” from the neurosteroid.

In the course of this “withdrawal”, certain GABA_(A) receptor subunitsmay be expressed, or suppressed, in a manner that causes the person'sbrain to be susceptible to greater feelings of anxiety. In particular,his brain's GABA_(A) receptor α₁ subunits decrease in relative amountsto GABA_(A) receptor α₄ subunits. As a result of neurosteroid“withdrawal” and the subsequent up-regulation of α₄ subunits relative toα₁ subunits, the GABA receptor is no longer effectively modulated byGABA, and, therefore, results in the person experiencing a greater senseof anxiety.

In one embodiment, an individual's lowered degree of inhibitory controlover his thoughts is caused by the modification of the receptivity ofthe synaptic GABA_(A) receptors to the neurotransmitter GABA in theindividual's brain. For example, substance abuse diminishes GABAreceptivity; thus, the exogenous substance or “drug” modulates theGABA_(A) receptor. When the user ceases consumption of the exogenoussubstance, due to changes in the GABA_(A) receptor composition uponwithdrawal (i.e. increased relative amount of GABA_(A) receptor α₄subunits compared to GABA_(A) receptor α₁ subunits), the receptor is noteffectively modulated by GABA, thus causing anxiety.

FIG. 1 illustrates the spectrum between inhibition and disinhibition viathe direct and/or indirect allosteric modulation of GABA_(A). Spectrum100 further depicts the range between inhibition 105 and disinhibition110. An increase in an exogenous or endogenous substance that directlyor indirectly enhances the function of GABA or the GABA_(A) receptor 115can result in an increase in GABA agonism and thus an increase ininhibition, anxiolysis, amnesia, and sedation, and even a comatosestate.

However, as mentioned in greater detail above, stress, drug use, andeven behavior activates these adaptive responses and disruptshomeostasis—the brain's internal balance. Upon withdrawal of bothendogenous and exogenous substances, there is a marked increase in theα₄ subunit 120 of relative to the α₁ subunit 125 of the GABA_(A)receptor 115, as shown in spe0ctrum 150. The increase of the α₄ subunit120 of the GABA_(A) receptor 115 causes the receptor to becomeinsensitive to benzodiazepines and other compositions that act uponand/or enhance the function of GABA and the GABA_(A) receptor.Therefore, when the systems involved in allostasis do not self-regulate(i.e. do not shut off when not needed or do not activate when needed),the brain experiences a compensatory drive to address this inactive orconstantly active state, often exhibited in the form of anxiety orcravings.

IV. Anxiety and Inhibition

Anxiety may be defined in a plurality of ways, including a vagueunpleasant emotion that is experienced in anticipation of some, oftenill-defined misfortune, a complex combination of the feeling of fear,apprehension and worry often accompanied by physical sensations such aspalpitations, chest pain and/or shortness of breath, a feeling ofapprehension, fear, nervousness, or dread accompanied by restlessness ortension, and/or a debilitating condition of fear, which interferes withnormal life functions. Anxiety is evaluated clinically using diagnosticinventories such as the Hamilton Anxiety Rating Scale (Guy, William,“048 HAMA Hamilton Anxiety Scale,” ECDEU Assessment Manual, U.S.Department of Health and Human Services, Public Health Service—Alcohol,Drug Abuse, and Mental Health Administration, Rev. 1976, pp. 194-198) orthe Beck Anxiety Inventory (Encephale. 1994 January-February; 20(1):47-55), which are herein incorporated by reference.

In one embodiment, anxiety comprises a physiological state in which anindividual has a lowered degree of inhibitory control over his thoughts,as described above with respect to FIG. 1. Such lowered degree ofinhibitory control may be caused by the turning off, inhibition, orotherwise down-modulation of an internal thought filtering mechanism inthe person's brain. Referring to FIG. 2, the internal thought filteringmechanism 200 comprises certain centers within a person's prefrontalcortex 205, including the orbitofrontal cortex 210, which is consideredresponsible for exerting control, and the anterior cingulate 215, whichis considered responsible for motivation and drive impulses. These braincenters are substantially affected by certain physiological inputs, suchas a reward circuit that comprises the nucleus accumbens 220 and ventraltegmental 225 areas of the brain.

When normally regulated, the orbitofrontal cortex 210 can exert controlover a person's thoughts and avoid having an individual feel“overwhelmed” by vague, unpleasant emotions and feelings of fear,apprehension and worry. If GABA_(A) receptor functionality is somehowimpaired, however, GABA dysregulation occurs and can result in animpaired ability of the orbitofrontal cortex 210 to exert control over aperson's thoughts and, therefore, a lowered degree of inhibitorycontrol.

Consequently, the individual becomes compulsively driven to “address”this anxiety by making sure he obtains whatever substance, or engage inwhatever activity, his brain believes it needs in order to eliminate thefeelings of anxiety, e.g. regain inhibitory control over his thoughts.Therefore, it is the physiological drive to address feelings of anxietythat causes an individual to consciously engage in behavior which couldbe classified as self-destructive, such as substance abuse.

In the absence of a solution to address anxiety, a person is in aconstant stress response state which, both psychologically andphysiologically, directs the person to search for and obtain a solutionto the anxiety. Many indications are implicated as being caused by thephysiological drive to address feelings of anxiety. As discussed below,certain indications are caused by the psychological addiction andphysiological dependence upon various substances, both exogenous andendogenous.

Exogenous substances, such as opioids, benzodiazepines, cannabis,caffeine, nicotine, and other drugs, directly or indirectly affectGABA_(A) receptor functionality and, when those exogenous substances arewithheld from an individual, cause the expression of the GABA_(A)receptor α₄ subunit (hereinafter generally referred to as the α₄subunit) to increase relative to the expression of the α₁ subunit.

In particular, during use, such substances may directly or indirectlystimulate GABA_(A) via a neurosteroid mediated pathway. When thosesubstances are later withheld, the amount of α₄ subunits relative to α₁subunits increases. This ratio change is often temporary and is subjectto reversal. However, a distinct pathophysiology emerges when it becomesnon-reversing, namely when α₄ subunits no longer down-regulate relativeto α₁ subunits. As described above, when such pathophysiology getsestablished, the GABA_(A) receptor therefore becomes less sensitive tobenzodiazepines and effectively, modulation by the neurotransmitterGABA, and is less capable of exerting inhibitory control over anindividual's thoughts and behavior.

In one embodiment, it is possible to calculate a GABA-active steroidscore (“GS Score”) for nearly all substances. For every substance thatcrosses the blood brain barrier, or is active on the central nervoussystem, there is a minimum threshold level needed of that particularsubstance to effectively raise levels of GABA-active steroids. Thus, theGS Score correlates direct agonism of GABA_(A) and the indirectmodulation of GABA_(A) via a neurosteroid mediated pathway, such as, butnot limited to allopregnanolone. For example, but not limited to suchexample, cocaine has a lower GS Score than aspartame, since cocaine ismore potent and it takes a lower threshold dose of cocaine to raiselevels of GABA-active steroids. The GS Score is a methodology formeasuring and assigning a numeric value to the relative addictiveproperties of substances.

Referring to FIG. 3 a, a benzodiazepine sensitive GABA_(A) receptor 300a is shown. The GABA_(A) receptor comprises a plurality of subunits,including two β₂ subunits 305 a, a γ₂ subunit 310 a, and two α₁ subunits315 a. By affecting the functionality and expression of receptor subunitmRNAs, certain endogenous and exogenous substances cause the expressionof the GABA_(A) receptor α₄ subunit to increase relative to theexpression of the α₁ subunit. Referring to FIG. 3 b, the modifiedGABA_(A) receptor 300 b comprises a plurality of subunits, including twoβ₂ subunits 305 b, a γ₂ subunit 310 b, and two α₄ subunits 315 b. Asshown in FIG. 3 c, the GABA_(A) receptor therefore becomes lesssensitive to benzodiazepines and effectively, modulation by theneurotransmitter GABA, and is less capable of exerting inhibitorycontrol over an individual's thoughts and behavior.

Endogenous substances may also have similar effects. Specifically,GABA-modulatory steroids, such as progesterone and deoxycorticosterone(DOC) and their metabolites allopregnanolone andtetrahydrodeoxycorticosterone respectively, affect GABA_(A) receptorfunctionality and thus, when progesterone or DOC is decreased or“withdrawn” in an individual, cause the expression of the GABA_(A)receptor α₄ subunit to increase relative to the expression of the α₁subunit.

In addition, an increase in the level of endogenous neurosteroid isassociated with tolerance. Thus, engaging in activities that increaseneurosteroid production is an often temporary solution, because asdescribed above, a distinct pathophysiology emerges and when it becomesnon-reversing, namely when α₄ subunits no longer down-regulate relativeto α₁ subunits. This loss of inhibitory control impairs an individual'sability to act on cravings and thus contributes to irrational behaviorto engage in activities regardless of consequences.

Many systems within the body are subject to inhibitory control viaGABAergic neurons located in the brain. In the event that an endogenoussystem is subject to inhibitory feedback by GABA, then the dysregulationof GABA_(A) receptors can result in reduced inhibition or disinhibitionof that particular system. Thus, it can be determined whether a primarysystem is dysregulated, and thus disinhibited, often noted because apatient exhibits a particular indication or disease state, and morespecifically, a disease state where higher levels of an endogenousmarker are present. For example, but not limited to such example,abnormal cholesterol levels are indicative of dysregulation of a primarysystem. If, however, a primary system is not dysregulated, then it canbe determined whether an inhibitory system is disinhibited ordysregulated, and whether that inhibitory system is restored in thepresence of endogenous neurosteroids, such as allopregnanolone andprogesterone.

For example, but not limited to such example, prolactin inhibitsdopamine, and thus when a patient presents with lower levels ofdopamine, it is suggested that prolactin is not being subjected toinhibitory feedback, resulting in increased levels of prolactin.Increased levels of prolactin may be, at least in part, due to GABA_(A)receptor dysregulation, and thus disinhibition.

V. Compositions Used in the Novel Treatment Methodologies of the PresentInvention

The compositions described herein, and the compounds identified throughthe screening methodologies described herein, are intended to be used asdrugs in the treatment methodologies described below. As used in thisdescription, the term drug is used to refer to prescription ornon-prescription pharmaceutical compositions and/or medications thatinclude an active ingredient and, optionally, non-active, buffering, orstabilizing ingredients, including pharmaceutically acceptable carriersor excipients suitable for the form of administration of saidpharmaceutical compositions. It should be appreciated that theadministration of the drug may be achieved through any appropriate routeof administration, for example, orally, inhaled, anally, sublingual,bucally, transdermally, nasally, implant, or parenterally, for which itwill be formulated using the appropriate excipients for the form ofadministration.

Table 1 is attached hereto and offers an exemplary listing ofpharmacological compounds in the classes of compounds described herein.It should be noted however, that Table 1 is not an exhaustive list ofall of the compositions that can be used with the present invention andthat the present invention is not limited to the use of such compounds.

a. Compounds that Inhibit Neurosteroid Production

In one embodiment, the present invention is directed towards a method ofusing a compound from a class of compounds that inhibit neurosteroidproduction (“Inhibitors of Neurosteroid Production”). In one embodiment,the compound is one that inhibits the conversion of progesterone to itsmetabolite allopregnanolone. In another embodiment, the compound is onethat inhibits the conversion of progesterone metabolite5α-dihydroprogesterone into allopregnanolone.

As shown in FIG. 4, progesterone is first converted to5α-dihydroprogesterone via an enzyme called 5α-reductase.5α-dihydroprogesterone is then converted to 5α,3α-pregnanolone(allopregnanolone) via the 3α-hydroxysteroid oxidoreductase enzyme.

Reference will now be made to specific classes of inhibitors ofneurosteroid production for use in the present invention. While theclasses and inhibitors of neurosteroid production are describedgenerally herein, it should be understood to those of ordinary skill inthe art that any number of inhibitors of neurosteroid production thatprevent the conversion of progesterone into its metaboliteallopregnanolone can be used in the present invention and that the listis not exhaustive.

In one embodiment, an individual is administered a therapeuticallyeffective amount of a 5-alpha-reductase inhibitor which blocks theconversion of progesterone into allopregnanolone. One exemplary5-alpha-reductase inhibitor is finasteride or analogs or derivativesthereof. Preferably, the 5α-reductase inhibitor is capable of acting asa Type I inhibitor, a Type II inhibitor, or a combination thereof, andinhibits the 5α-reductase enzyme from converting progesterone to5α-dihydroprogesterone and thus from creating progesterone metaboliteallopregnanolone.

There are currently accepted dosing regimens for 5-alpha-reductaseinhibitors. The present invention contemplates operating within themaximum limits of currently accepted dosing regimens in order tomaximally decrease the production of allopregnanolone and make theindividual most receptive to treatment.

In one embodiment, an individual is administered a therapeuticallyeffective amount of a 3-alpha-hyrodxysteroid oxidoreductase inhibitorwhich blocks the conversion of progesterone metabolite5α-dihydroprogesterone into allopregnanolone. One exemplary3-alpha-hyrodxysteroid oxidoreductase is indomethacin or analogs orderivatives thereof. There are currently accepted dosing regimens for3-alpha-hyrodxysteroid oxidoreductase inhibitors. The present inventioncontemplates operating within the maximum limits of currently accepteddosing regimens in order to effectively decrease the production ofallopregnanolone and make the individual most receptive to treatment.

Bitran et al (1995) have demonstrated that treatment with a5-alpha-reductase inhibitor prevents the conversion of progesterone toallopregnanolone and eliminates the anxiolytic activity of progesterone.In addition, it has been suggested that the anxiogenic withdrawalproperties of allopregnanolone can be prevented by previousadministration of a 3α-hydroxysteroid oxidoreductase blocker such asindomethacin.

i. 5α-Reductase Inhibitors

The 5α-reductase inhibitors are a group of drugs with anti-androgenicactivity that effectively decrease the amount of the 5α-reductase enzymeand thus inhibit neurosteroid production.

1. Finasteride

Finasteride is a synthetic 4-azasteroid compound, and is a5alpha-reductase inhibitor. Finasteride is4-azaandrost-1-ene-17-carboxamide,N-(1,1-dimethylethyl)-3-oxo-,(5α,17β)-.The empirical formula of finasteride is C₂₃H₃₆N₂O₂ and its molecularweight is 372.55.

Finasteride is a competitive and specific 5α-reductase inhibitor.Finasteride has no affinity for the androgen receptor and has noandrogenic, antiandrogenic, estrogenic, antiestrogenic, orprogestational effects.

Progesterone is metabolically converted to the GABA_(A)receptor-potentiating neuroactive steroid allopregnanolone by5α-reductase isoenzymes followed by 3α-hydroxysteroid oxidoreduction.Finasteride acts as a competitive 5α-reductase inhibitor and thus blocksthe production of allopregnanolone from progesterone.

In one embodiment, finasteride is delivered using at least one oraltablet with a total daily dose of less than 10 mg, preferably less than5 mg. It should be appreciated that, to the extent approved byregulatory authorities, finasteride can also be delivered in gelcapsules or via injection or infusion. Finasteride should not be used bywomen of childbearing age. Finasteride's side effects include breastenlargement and tenderness, skin rash, swelling of lips, abdominal pain,back pain, decreased libido, decreased volume of ejaculate, diarrhea,dizziness, headache, impotence, and testicular pain.

2. Dutasteride

Dutasteride is a synthetic 4-azasteroid compound that is a selectiveinhibitor of both the Type I and Type II isoforms of the steroid5α-reductase, an intracellular enzyme. Dutasteride is chemicallydesignated as (5α,17β)-N-{2,5bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide. Theempirical formula of dutasteride is C₂₇H₃₀F₆N₂O₂, representing amolecular weight of 528.5.

As a competitive Type I and Type II 5α-reductase inhibitor, dutasterideinhibits the conversion of progesterone to allopregnanolone. Dutasteridedoes not bind to the human androgen receptor.

In one embodiment, dutasteride is delivered using at least one capsulewith a total daily dose of less than 10 mg, preferably less than 0.5 mg.It should be appreciated that, to the extent approved by regulatoryauthorities, dutasteride can also be delivered in tablets or viainjection or infusion. Dutasteride should not be used by women ofchildbearing age. Dutasteride's side effects include cough, difficultyswallowing, dizziness, fast heartbeat, hives or welts, itching skin,puffiness or swelling of the eyelids or around the eyes, face, lips, ortongue, redness of skin, shortness of breath, skin rash, swelling offace, fingers, feet, and/or lower legs, tightness in chest, unusualtiredness or weakness, wheezing, abnormal ejaculation, decreasedinterest in sexual intercourse, decreased sexual performance or desire,impotence, inability to have or keep an erection, loss in sexualability, desire, drive, or performance, or swelling of the breasts orbreast soreness.

3. Other 5α-Reductase Inhibitors

The present invention also encompasses the use of other 5-alphareductase inhibitors, including a) 4-aza-4-methyl-5alpha-pregnane-3,20-dione (AMPD), which inhibits pituitary progesterone5-alpha reduction, b) cyproterone acetate, and c) spironolactone, whichis a diuretic that blocks two pathways to the production of androgens,or male hormones, one of which is the inhibition of 5α-reductase.

The present invention also encompasses the use of organic sources of5-alpha reductase inhibition, including organic sources such as sawpalmetto. Saw palmetto (Serenoa repens) is a natural source of a5α-reductase inhibitor. Some studies suggest that it may be comparableto finasteride if taken for six months. Saw Palmetto is advantageousbecause it is 1) substantially free of side effects and 2) costeffective.

ii. Other Inhibitors of Neurosteroid Production

The present invention further includes the use of 3α-hydroxysteroidoxidoreductase blockers. Gallo and Smith (1993) suggest that theanxiogenic withdrawal property of progesterone could be prevented byprevious administration of a 3α-hydroxysteroid oxidoreductase blocker.In one embodiment, indomethacin is used. Indomethacin is a non-steroidalanti-inflammatory drug (NSAID) that reduces fever, pain andinflammation. It is similar to ibuprofen and naproxen. Indomethacin iseffective in reducing the production of prostaglandins.

It should be appreciated that any composition that can be used toinhibit neurosteroid production can be used in the present invention. Inone embodiment, compounds are preferably screened to determine whetherthey can be used in the treatment methodologies of the presentinvention.

Specifically, an appropriate cellular model is used to model theinhibition of neurosteroid production. The efficacy of the compositionis measured by measuring the relative levels of progesterone andallopregnanolone in a model prior to the administration of thecomposition and after the administration of the composition. In caseswhere the relative levels of progesterone and allopregnanolone decreaseafter administration, the composition may be suitable as an inhibitor toneurosteroid production.

b. Compounds that Modulate the Expression of Certain GABA_(A) ReceptorSubunits

Molecular biology studies have revealed a high degree of structuralheterogeneity of the GABA_(A) receptors. Development of subtypeselective or specific compounds is of key importance for theunderstanding of the physiological and pathological roles of differentGABA receptor subtypes and may lead to valuable therapeutic agents. Ithas been shown that functional selectivity is obtainable for a number ofGABA_(A) agonists.

Characterizations of the role of GABA_(A) receptors require anunderstanding of the mechanisms by which subunit composition isregulated. The long-term administration of sedative-hypnotic,anxiolytic, or anticonvulsant drugs can affect expression of GABA_(A)receptor subunit genes as well as the drug sensitivity and function ofthese receptors, suggesting that the mechanisms responsible for suchchanges might also underlie the physiological modulation of GABA_(A)receptors by endogenous compounds such as neurosteroids.

The level of efficacy of a partial agonist/antagonist depends upon thedisease or dependence in question. Thus, by measuring the level ofefficacy or activity of a partial agonist/antagonist at a receptor site,it is possible to determine what the disease state is and determine whatconformational changes have occurred in the GABA_(A) receptor subunits.Based upon this information, certain compositions can be classifiedaccording to the changes they cause in GABA_(A) subunits. In addition,since the GABA binding site in the GABA_(A) receptor is located at theinterface between α and β subunits, the GABA_(A) antagonists can bind toand stabilize a distinct inactive receptor conformation.

The present invention is thus directed towards a class of compounds thatmodulates the expression of certain GABA_(A) receptor subunits. Morespecifically, the compound is one that serves as an agonist at theGABA_(A) receptor, and more specifically, at either the α₄ subunit or α₆subunit, and is capable of positively potentiating GABA current.

Still more specifically, the compound of choice is one that a) acts apartial agonist of GABA_(A); b) inhibits the up-regulation of the α₄subunit and/or increases the amount of the al subunit relative to theamount of the α₄ subunit; and c) does not cause the up-regulation of theα₄ subunit and/or does not cause the amount of the α₄ subunit toincrease relative to the amount of the α₁ subunit once the compound isno longer present in the patient's system.

The changes in expression of the GABA_(A) receptor α₄ subunit relativeto the GABA_(A) receptor α₁ subunit can be attributed to many factors.These include, but are not limited to 1) compositions, both endogenousand exogenous, that transform the GABA_(A) receptor α₄ subunit relativeto the GABA_(A) receptor α₁ subunit and vice versa; 2) compositions thatresult in the decrease of expression of the GABA_(A) receptor α₄ subunitor the increase of expression of the GABA_(A) receptor α₁ subunit; and3) compositions that do not modify existing subunit levels, but ratherprevent the upregulation of GABA_(A) receptor α₄ subunit.

Thus, the compound of choice is one that effectuates an increase in theexpression of the GABA_(A) receptor α₁ subunit relative to theexpression of the α₄ subunit. This increase in expression of the alsubunit may be effectuated by one or more of the following: a)upregulating the expression of α₁ subunits; b) downregulating theexpression of α₄ subunits; c) masking α₄ subunits; or d) preventing theupregulation of the α₄ subunit.

The focus is thus on using a compound from the class of compounds thatmodulates the expression of certain GABA_(A) receptor subunits, and morespecifically, moves the relative balance of the α₄ subunit to the α₁subunit closer to a normal state from an abnormal, allostatic state.

i. Flumazenil

In one embodiment, the present invention relates to the use of atherapeutically effective quantity of a drug, and more specifically, onethat modulates the expression of GABA_(A) subunits, such as, but notlimited to, flumazenil, in a methodology for treatment of substanceabuse. In one embodiment, the compound may comprise certainimidazobenzodiazepines and derivatives of ethyl8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo-[1,5-a][1,4]benzodiazepine-3-carboxylate, including various substitutions of thecarboxylate functional group, such as carboxylic acids, esters, acylchlorides, acid anhydrides, amides, nitrites, alkyls, alkanes,cycloalkanes, alkenes, alcohols, aldehydes, ketones, benzenes, phenyls,and salts thereof. In another embodiment, the compound comprisesflumazenil or carboxylic acids, esters, acyl chlorides, acid anhydrides,amides, nitrites, alkyls, alkanes, cycloalkanes, alkenes, alcohols,aldehydes, ketones, benzenes, phenyls, and salts thereof.

Flumazenil acts a partial agonist of GABA_(A), inhibits the upregulationof the α₄ subunit and/or increases the amount of the al subunit relativeto the amount of the α₄ subunit, and does not cause the upregulation ofthe α₄ subunit and/or does not cause the amount of the α₄ subunit toincrease relative to the amount of the α₁ subunit once the compound isno longer present in the patient's system.

ii. Miltirone

In another embodiment, the compound may comprise miltirone, as describedin Mostallino et al., “Inhibition by miltirone of up-regulation ofGABA_(A) receptor α₄ subunit mRNA by ethanol withdrawal in hippocampalneurons”, European Journal of Pharmacology, 494 (2004) 83-90.

iii. Flavonoids

In another embodiment, the compound may comprise certain flavonoids thatact as a partial agonist of GABA_(A), inhibit the upregulation of the α₄subunit and/or increase the amount of the α₁ subunit relative to theamount of the α₄ subunit, and does not cause the upregulation of the α₄subunit and/or does not cause the amount of the α₄ subunit to increaserelative to the amount of the α₁ subunit once the compound is no longerpresent in the patient's system.

It should be appreciated that any composition that can function asdescribed above, can be used in the present invention. In oneembodiment, compounds are preferably screened to determine whether theycan be used in the treatment methodologies of the present invention. Inone embodiment, experiments are conducted to determine whether itfunctions as a partial agonist of GABA_(A), inhibits the upregulation ofthe α₄ subunit, and does not cause the upregulation of the α₄ subunitonce the compound is no longer present in the patient's system. Whileone of ordinary skill in the art can devise such experiments, anexemplary embodiment of such an experiment is provided in Mostallino etal., “Inhibition by miltirone of up-regulation of GABA_(A) receptor α₄subunit mRNA by ethanol withdrawal in hippocampal neurons”, EuropeanJournal of Pharmacology, 494 (2004) 83-90.

VI. Novel Treatment Methodologies

The present invention is directed towards a comprehensive treatmentprotocol that employs methods of, and compositions for, preparing apatient for treatment and modulating the expression of certain GABA_(A)receptor subunits. The present invention therefore treats withdrawalsymptoms associated with psychological addiction and physiologicaldependence upon various exogenous and endogenous substances in thecontext of a comprehensive treatment plan of behavioral and/orpharmacological treatment.

The multiple phase treatment methodology of the present inventionemploys one or more compounds to reset physiochemical changes in apatient that is experiencing withdrawal from addictive and/ordependency-inducing substances, including but not limited to opioids andderivatives, nicotine, benzodiazepines, caffeine, cannabis, oranti-depressant drugs. Effective treatment of such indications requiresaddressing the maladaptive behaviors underlying addiction andphysiological dependence upon various exogenous substances, namely theincreased expression of the GABA_(A) receptor α₄ subunit relative to theα₁ subunit.

The treatment methodology of the present invention thus incorporates 1)determining if a person is in a receptive state for treatment and/orcausing a person to be in a receptive state for treatment and 2)treating a person using appropriate drugs in a comprehensive treatmentprotocol that includes pre-drug assessment including optionaldetoxification, treatment, and aftercare. The term “receptive state”, asused herein, refers to a physiological state in which the patient iswithdrawn from both endogenous and exogenous substances.

As used in this description, the term “substance abuse” is used to referto the various physical and psychological states that manifest anindividual's impaired control over substance use, continued substanceuse despite adverse consequences, compulsive substance use, and/or drugcravings. The term is intended to include psychological dependence,physical dependence, tolerance, a maladaptive pattern of substance use,preoccupation with substance use, and/or the presence of withdrawalsymptoms upon cessation of use. Notwithstanding the above, the terms“addiction” and “dependency” are used interchangeably throughout thistext. While it is traditionally understood that addiction and dependencyrelate to illegal or narcotic substances, it should be understood herethat the treatment protocol of the present invention may also be used totreat other drug addictions, withdrawal reaction from prescribedmedication, and other types of compulsive behaviors relating to food,sex, or gambling.

As used in this description, the term “substance” refers to acomposition to which a person may exhibit withdrawal symptoms fromabrupt cessation of intake or production of the composition, andincludes, but is not limited to, opiates, nicotine, benzodiazepines,caffeine, cannabis, and anti-depressants.

As used in this description, the term patient refers to a male or femalehuman being of any race, national origin, age, physiological make-up,genetic make-up, disease predisposition, height, or weight, and havingany disease state, symptom or illness.

It should further be appreciated that the methods and processes of thepresent invention can be implemented in a computer system having a datarepository to receive and store patient data, a memory to store theprotocol steps that comprise the methods and processes of the presentinvention, a processor to evaluate patient data in relation to saidprotocol steps, a network interface to communicate via a network withother computing devices and a display to deliver information to users.In one embodiment, specific protocol steps are stored in said memory andcompared against patient data, including behavioral, psychological orphysiological profiles, to determine which protocol steps should beapplied. Results of the comparison are communicated to a user via anetwork and other computing devices or display. The methodologies of thepresent invention are therefore accessed, tailored, and communicated asa software program operating on any hardware platform.

The exemplary treatment methodology of the present invention comprisespre-treatment, co-treatment, and post-treatment phases furthercomprising various components of an exemplary methodology.

As described herein, reference will be made to specific components ofthe individual phases of the treatment methodology. It should be noted,however, that the individual components comprising each phase of themethodology—pre-treatment, co-treatment, and post-treatment—areinterchangeable and may be performed variably, and should be determinedon a per-patient basis. Thus, any reference to administering theindividual components of the phases of methodology in a particular orderis exemplary and it should be understood to one of ordinary skill in theart that the administration of methodology may vary depending on theassessed needs of the patient. Furthermore, while the invention will bedescribed in conjunction with specific embodiments, it is not intendedto limit the invention to one embodiment. In addition, many combinationsof the methodology components described above are possible; thus, theinvention is not limited to such examples as provided.

The treatment protocols will first be generally described and thenspecific examples of the treatment protocols will be providedthereafter.

a. Pre-Treatment/Patient Assessment Phase

Prior to admittance into the treatment program of the present invention,each patient should undergo a pre-treatment analysis. The pre-treatmentanalysis may be used to determine whether a patient is a candidate forthe treatment methodology of the present invention. In addition, thepre-treatment process may be administered to prepare a patient foradmittance into the treatment methodology of the present invention. Thepre-treatment phase typically includes, but is not limited to a medicalhistory and physical examination, a psychological and behavioralassessment, a determination of required medications, and detoxificationif needed to render the patient in a state receptive to treatment.

The treatment methodology for substance abuse has multiple phases andcomponents that, in combination, provide a comprehensive and integratedneurological, physiological, and psychosocial approach for thesubstance-dependent patient. Each component has been selected to addressspecific effects of chronic substance use and the corresponding symptomsof withdrawal, with the objective of restoring a balance in neurologicalcircuits. The methodology does not address the specific physical injuryoften associated with substance dependence. It is, therefore, essentialthat each patient be assessed and the appropriate treatments beinstituted to address physical injury, with due consideration for thepotential interaction of any medicaments used for this treatment withthose used for the dependency treatment.

While the present methodology can be applied to any patient, it ispreferred that the patient be equal to or greater than eighteen yearsold.

i. Complete Physical Examination

Before starting the treatment, the patient undergoes a medical history,physical examination and laboratory assessment, including but notlimited to a complete blood count, a biochemical profile [for example,creatinine, glucose, urea, cholesterol (HDL and LDL), triglycerides,alkaline phosphatase, LDH (lactic dehydrogenase) and total proteins],hepatic function tests [GOT, GPT, GGT, bilirubin), electrocardiogramand, if appropriate, pregnancy test and x-ray examinations. Exclusioncriteria are applied to ensure no other acute or uncompensated illnessexists within the patient and to ensure that the patient does notrequire, or is currently not taking, a drug that is contraindicated withthe GABA_(A) receptor modulating compound being used.

i. Diagnosis of Substance Abuse, Dependence, and Tolerance

It is preferred that the patient meet at least a portion of recognizedcriteria for dependence on a particular substance, such the DSM-IVcriteria. The DSM-IV criteria is known to those of ordinary skill in theart and can be described as a maladaptive pattern of substance use,leading to clinically significant impairment or distress, as manifestedby any of the following, occurring at any time in the same 12-monthperiod:

-   -   Tolerance, as defined by either of the following:        -   A need for markedly increased amounts of the substance to            achieve intoxication or desired effect.        -   Markedly diminished effect with continued use of the same            amount of the substance.    -   FULL WITHDRAWAL, as manifested by either of the following:        -   The characteristic withdrawal syndrome for the substance.        -   The same (or a closely related) substance is taken to            relieve or avoid withdrawal symptoms.        -   Physiological Determination (as described in greater detail            below)    -   The substance is often taken in larger amounts or over a longer        period than was intended (loss of control).    -   There is a persistent desire or unsuccessful efforts to cut down        or control substance use (loss of control).    -   A great deal of time is spent in activities necessary to obtain        the substance, use the substance, or recover from its effects        (preoccupation).    -   Important social, occupational, or recreational activities are        given up or reduced because of substance use (continuation        despite adverse consequences).    -   The substance use is continued despite knowledge of having a        persistent or recurrent physical or psychological problem that        is likely to have been caused or exacerbated by the substance        (adverse consequences).

It should further be noted that certain exclusion criteria should beapplied to the screening of patients. The exclusion criteria may betailored to an outpatient or inpatient treatment scenario. For example,it is preferred not to treat a patient on an inpatient basis forsubstance abuse or dependence where the patient has current medical orpsychiatric problems that, per the screening physician, requireimmediate professional evaluation and treatment, has current medical orpsychiatric problems that, per the screening physician, render theclient unable to work successfully with the methodology or with thestaff administering the treatment, has current benzodiazepine and othersedative-hypnotic-anxiolytic use (urine toxicology must be negative) oris taking anti-psychotic medication(s).

b. Preparing a Patient for Treatment with the Protocol of the PresentInvention (“Receptive State for Treatment”)

It should be noted, however, that the individual components comprisingthe preparation phase of the methodology are interchangeable and may beperformed variably, and should be adapted to the patient. Thus, anyreference to administering the individual components of the preparationphase of the methodology in a particular order is exemplary and itshould be understood to one of ordinary skill in the art that theadministration of methodology may vary depending on the assessed needsof the patient. In addition, many combinations of the methodologycomponents described above are possible; thus, the invention is notlimited to such examples as provided.

i. Placing a Patient in a State of Withdrawal

As used herein, the term “withdrawal” refers to a physiological state inwhich an individual has begun to have adverse psychological and/orphysiological effects from not having a bioavailable amount ofparticular substance or from having a decreasing bioavailable amount ofa particular substance. More specifically, withdrawal can be attributedto an increase in the GABA_(A) receptor α₄ subunit expression relativeto the GABA_(A) receptor α₁ subunit.

The treatment methodologies of the present invention include a firststep of placing a patient in a state of withdrawal. In one embodiment, aperson is placed in a receptive state for treatment by activelyinhibiting the upregulation of endogenous neurosteroids and/or causingthe downregulation of endogenous neurosteroids. The upregulation ofneurosteroids could be caused by a number of external factors, includingthe ingestion or administration of certain substances, such as caffeineor nicotine, or psychological stress. The present invention thereforeincludes the step of avoiding all such activities that could result inthe upregulation of an individual's neurosteroid level.

In another embodiment, a person is placed in a receptive state fortreatment by actively causing the downregulation of endogenousneurosteroids, such as allopregnanolone, through the administration ofinhibitors of neurosteroid production that block the production ofendogenous neurosteroids and/or their metabolites. The present inventionalso includes the inhibition of the modulatory effects of neurosteroidson GABA_(A). By doing so, one accelerates the exposure or upregulationof α₄ subunits relative to α₁ subunits and ensures that a substantialnumber of α₄ subunits are exposed and available to enhance the efficacyof subsequent treatment steps.

In one embodiment, to place the patient in a state receptive totreatment, the patient is induced into a state of withdrawal from thesubstance upon which the patient is addicted or dependent. Thewithdrawal state can be initiated by withholding the substance or by aprocess of sequentially decreasing daily dosing of an agonist or partialagonist medication with similar pharmacological properties (e.g.methadone of buprenorphine for heroin dependence).

For example, but not limited to such example, in the case of opiatesubstance abuse or dependence, the opiate user is administered an opiateagonist that preferably has a longer half-life and is less potent thanthe drug to which the patient has an addiction. Appropriatemethodologies for titrating a person down from an addictive substanceare discussed in greater detail below with respect to exemplarytreatment protocols. Administration of certain compositions serves toflush the user's system and places the user in a physiological statecapable of effectively receiving an administration of a drug for thepurpose of alleviating cravings and other withdrawal symptoms.

Once a patient is no longer taking the addictive substance or hastitrated his dependence down to sufficiently low levels, the presentinvention further includes the step of actively causing thedownregulation of endogenous neurosteroids, such as allopregnanolone,through the administration of agents that block the production ofendogenous neurosteroids and/or their metabolites. The present inventionalso includes the inhibition of the modulatory effects of neurosteroidson GABA_(A). By doing so, one accelerates the exposure or upregulationof α₄ subunits relative to α₁ subunits and ensures that a substantialnumber of undesirable subunits are exposed and available for enhancedpharmacotherapeutic efficacy.

Particular methods for baselining endogenous neurosteroid production toa consistent level in the pre-treatment portion of the protocol arediscussed below, but the treatment protocol is not limited to suchmethods. For the methods listed below, the present inventioncontemplates operating in a dosing range of established safety andefficacy in order to maximally decrease the production of progesteroneand make the individual most receptive to treatment.

1. Avoid Stress-Inducing Activities

In one embodiment, the present invention includes the step of avoidingall such activities that could result in the upregulation of anindividual's neurosteroid level and the step of actively causing thedownregulation of endogenous neurosteroids, such as allopregnanolone. Itshould be noted that stress-inducing activities depend upon the patientand the patient's general condition. Thus, individual recommendationsmay be made by the treating physician.

2. Avoid Neurosteroid Production Enhancing Activities

The patient is advised to not engage in activities, or ingest anysubstances, that could likely increase neurosteroid production. Suchactivities include sex, stressful activities, fighting, or intensearguing. Such substances include chocolate, illegal drugs, prescriptiondrugs, or over the counter medicines.

Although not preferred because these compositions may serve to increaseneurosteroid production, in certain cases, it may be necessary toadminister a composition to reduce stress.

In one embodiment, the stress-reducing composition is gabapentin.Gabapentin is an anxiolytic and anticonvulsant medication typicallyprescribed to patients suffering from epilepsy (effectively lowers brainglutamate concentrations) and has also been used in the treatment ofanxiety disorders such as social anxiety disorder andobsessive-compulsive disorder. Prior to administering gabapentin to apatient, it is essential to assess the patient for interactions andcontraindications. Gabapentin is to be used in adjunctive therapy in thetreatment of epilepsy seizures (partial) and for the management ofpostherpetic neuralgia. Gabapentin is not appreciably metabolized and isexcreted unchanged with an elimination half-life of 5-7 hours. Possibleside effects from the use of gabapentin are dizziness, somnolence, othersymptoms/signs of CNS depression, nausea, ataxia, tremor, and peripheraledema. In persons with epilepsy, abrupt discontinuation may increaseseizure frequency. No clinically significant drug interactions have beenreported in the literature.

In another embodiment, the stress-reducing composition is a H1 histaminereceptor agonist, such as, but not limited to hydroxyzine. Hydroxyzineis indicated for treatment of generalized anxiety disorder symptoms andfor use in the management of withdrawal from substance dependence duringboth the initial phase of inpatient treatment and post-discharge care(as necessary). It also has anti-emetic and skeletal muscle relaxationbenefits and can be used as a sedative. This sedative effect can beuseful for treating the sleep-disordered breathing and increasedperiodic leg movements that contribute to the insomnia often seen inpatients recovering from alcohol dependency. This helps address on-goinginsomnia which, for some patients is significantly associated withsubsequent alcoholic relapse.

Hydroxyzine is rapidly absorbed and yields effects within 15-30 minutesafter oral administration. In addition, hydroxyzine aids the substancewithdrawal process through anxiolytic, anti-nausea, relaxant, andvarious other properties. It should be noted that the effects of othersedating or tranquilizing agents may be synergistically enhanced withthe administration of hydroxyzine. Exemplary trade names of these drugsinclude Atarax and Vistaril.

3. Avoid Heightened Progesterone Levels in Patient

In an optional embodiment, it is possible to minimize endogenousneurosteroid production by timing the treatment in a manner that avoidsheightened progesterone cycles.

In women, progesterone levels are low during the pre-ovulatory phase ofthe menstrual cycle, rise after ovulation, and are elevated during theluteal phase. Specifically, progesterone levels tend to be <2 ng/mlprior to ovulation, and >5 ng/ml after ovulation. If pregnancy occurs,progesterone levels are maintained at luteal levels initially. With theonset of the luteal-placental shift in support of the pregnancy,progesterone levels start to rise further and may reach 100-200 ng/ml atterm. After delivery of the placenta and during lactation, progesteronelevels are low.

For example, but not limited to such example, since progesterone levelsare highest during the luteal phase of the menstrual cycle, it ispreferred not to treat a woman during this time window. Conversely, itis preferred to treat a woman during the pre-ovulatory phase of themenstrual cycle, when progesterone levels are low.

Progesterone levels are low in children, men, and postmenopausal women.

4. Actively Modulate a Woman's Progesterone Levels

In another embodiment, a woman's progesterone is actively modulated bythe administration of prescription hormones, such as, but not limitedto, contraception with progesterone, that keeps the woman on a constantprogesterone level. Such contraception includes progestin implants andlevonorgestrel implants. Administration of these compositions willeffectively make a woman's progesterone levels constant.

Upon withdrawal of these contraception compositions, the woman's hormonelevel will decrease, thereby “unmasking” its α₄ receptor subunits andplacing a woman in a state most receptive to treatment.

The present invention advantageously uses the time gap between whenadministered progesterone leaves the system and when endogenousprogesterone production resumes. In one embodiment, this minimalprogesterone point window is preferably when the treatment protocol ofthe present invention should begin.

In one embodiment, progesterone can be delivered orally, sublingually,via vaginal suppositories, via injection, topically, transdermally, orby implant. The rate of absorption of progesterone is highly dependentupon the administration route. Irrespective of the type used,progesterone, progestin, or other progesterone-like compounds should beadministered in sufficient amounts to attain a heightened level ofprogesterone and then terminated in sufficient time to allow for theprogesterone levels to decrease prior to treatment.

It should again be noted that Table 1 offers an exemplary listing ofpharmacological compounds in the classes of compounds described herein.Several examples of contraception and recommended dosing parameters arealso listed in Table 1.

5. Actively Modulate a Male's or Female's Progesterone Levels

As mentioned above, various neurosteroid inhibitors prevent theconversion of progesterone into allopregnanolone. In an endogenous case,allopregnanolone is responsible for the modulation of the GABA_(A)receptors. By compensating for the effects of the withdrawn substance,endogenous neurosteroids, when elevated, “mask” GABA_(A) receptors andprevent flumazenil from being able to “re-set” those receptors. Theadministration of these drugs can effectively drive down endogenousneurosteroid levels.

In one embodiment, the compound is a 5α-reductase inhibitor. Preferably,the 5α-reductase inhibitor is capable of acting as a Type I inhibitor, aType II inhibitor or a combination thereof and inhibits the 5α-reductaseenzyme from converting progesterone to 5α-dihydroprogesterone and thusfrom creating progesterone metabolite allopregnanolone. In anotherembodiment, the compound is a 3α-hydroxysteroid oxidoreductaseinhibitor, which prevents the 3α-hydroxysteroid oxidoreductase enzymefrom converting 5α-dihydroprogesterone into 5α,3α-pregnanolone(allopregnanolone).

While the class of compounds that inhibit neurosteroid production hasbeen described in detail above, an exemplary list of compounds isdescribed in detail in Table 1. It should be noted, however, that thepresent invention is not limited to such compounds and any compoundsthat effectively inhibit endogenous neurosteroid production, and inparticular, the conversion of progesterone to its metaboliteallopregnanolone, can be used with the present invention.

ii. Industry-Standard Treatment Approaches

In one embodiment, the patient is subjected to standard and/orindustry-accepted treatment protocols. Several exemplary treatmentprotocols are detailed in the sections below. It should be noted,however, that the treatment protocols outlined herein are exemplary andany number of treatment protocols may be used with the present inventionprovided that they are not contraindicated with the use of a compoundfrom the class of compounds that permanently increases the relativeexpression of the α₁ GABA_(A) subunit relative to the α₄ GABA_(A)subunit.

Many of the conventional protocols described herein are adapted by theNational Guideline Clearinghouse. The National Guideline Clearinghouse™(NGC) is a comprehensive database of evidence-based clinical practiceguidelines and related documents. NGC is an initiative of the Agency forHealthcare Research and Quality (AHRQ), U.S. Department of Health andHuman Services. NGC was originally created by AHRQ in partnership withthe Americal Medical Association and the American Association of HealthPlans (now America's Health Insurance Plans [AHIP]). The NGC mission isto provide physicians, nurses, and other health professionals, healthcare providers, health plans, integrated delivery systems, purchasersand others an accessible mechanism for obtaining objective, detailedinformation on clinical practice guidelines and to further theirdissemination, implementation and use.

In addition, some clinical practice guidelines were adapted from theUnited States Department of Health and Human Services Substance Abuseand Mental Health Services Administration. More specifically, protocolswere adapted from the National Clearinghouse for Alcohol and DrugInformation.

Certain clinical practice guidelines were also adapted from the ExpertConsensus Guidelines are being used throughout the country byclinicians, policy-makers, administrators, case managers, mental healtheducators, patient advocates, and clinical and health servicesresearchers.

The use of industry-accepted treatment protocols is optional.

c. Administration of a Compound from the Class of Compounds thatModulates the Expression of Certain GABA_(A) Receptor Subunits

Whether used independently of, or part of, any other treatment approach,the present invention requires a patient to be administered a compoundfrom the class of compounds that modulates the expression of certainGABA_(A) receptor subunits, as described above. In one embodiment, thecompound serves as an agonist at the GABA_(A) receptor, and morespecifically, at either the 4 subunit or α₆ subunit, and is capable ofpositively potentiating GABA current.

It should be noted, however, that the present invention is not limitedto such subunit relative to the α₄ GABA_(A) subunit, in a non-transitorymanner, can be used with the present invention.

The present invention is directed towards, in one embodiment, the use ofa compound that modulates the expression of certain GABA_(A) receptorsubunits, such as flumazenil, in multiple doses for a predetermined timeperiod as part of the treatment methodology. When administered inaccordance with the present invention, a therapeutically effectiveamount of the drug is maintained in the patient, thereby significantlyreducing the upregulation of allopregnanolone. The methodology of thepresent invention also provides for the administration of a compoundthat modulates the expression of certain GABA_(A) receptor subunits,such as flumazenil, without significant side effects.

Thus, in one embodiment, a method is provided for the treatment ofsubstance abuse that includes the administration to a patient in need ofsaid treatment of a therapeutically effective quantity of flumazenil inmultiple doses during predetermined time periods/intervals, until atherapeutically effective quantity of flumazenil to treat substanceabuse has been reached, as measured by quantitative and/or qualitativeassessments of, for example, a patient's blood pressure, heart rate,feelings of cravings, and feelings of anxiety. Thus, it is possible toadminister flumazenil in variable doses to obtain the desiredtherapeutic response, reducing the risk of secondary effects in thepatient (as a result of reducing the quantity of drug administered perdose applied).

In another embodiment, a method is provided for the treatment ofsubstance abuse that includes the administration to a patient in need ofsaid treatment of a therapeutically effective quantity of flumazenil,usually between 0.5 mg/day and 20 mg/day, between 0.5 mg/day and 15mg/day, specifically between 1.0 and 3.0 mg/day, and more specificallybetween 1.5 and 2.5 mg/day, of flumazenil, broken down into multipledoses of flumazenil between 0.1 and 0.3 mg and intended foradministration during predetermined time periods or intervals, untilsaid therapeutically effective quantity of flumazenil to treat substanceabuse has been reached. In one embodiment, the predetermined time periodis in the range of 1 and 15 minutes and the “per dose” quantity offlumazenil is between 0.1 and 0.3 mg.

One of ordinary skill in the art would appreciate that the individualdoses can range in amount, and the time interval between the individualdoses can range in amount, provided that the total dose delivered is inthe range of 1.0 mg/day and 3.0 mg/day and the individual doses aredelivered at relatively consistent time intervals. Therefore, the timeperiod intervals can range from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 minutes orfractions thereof. Doses delivered at each time period, separated by thetime intervals, can be between 0.1 and 0.3 mg, or fractions thereof,keeping in mind the total drug delivered is preferably less than 3.0mg/day. The present invention therefore provides for the delivery ofmultiple, sequential doses, delivered at substantially consistent timeintervals.

Conventional uses of flumazenil comprise either singular doses or muchlarger doses over shorter periods of time and are directed towardreversing sedative effects of anesthesia, conscious sedation, orbenzodiazepine overdose. Further, Romazicon, a brand name for flumazenilmarketed by Roche, is expressly indicated to complicate the managementof withdrawal syndromes for alcohol, barbiturates and cross-tolerantsedatives and was shown to have an adverse effect on the nervous system,causing increased agitation and anxiety. For a single dose to addressanesthesia and conscious sedation, it is conventionally recommended touse a dose of 0.2 mg to 1 mg of Romazicon with a subsequent dose in noless than 20 minutes. For repeat treatment, 1 mg doses may be deliveredover five minutes up to 3 mg doses over 15 minutes. In benzodiazepineoverdose situations, a larger dose may be administered over shortperiods of time, such as 3 mg doses administered within 6 minutes. Oneof ordinary skill in the art would appreciate that such conventionaluses of flumazenil are not directed toward the treatment of substanceabuse.

In addition, the administration method of the present invention providesa better use of flumazenil to treat the symptoms of substance abusewithdrawal and to reduce the unnecessary consumption of said drug,thereby increasing convenience and the quality of life of the patientand reducing cost, to treat substance abuse in a very short period oftime.

The method for the treatment of substance abuse provided by thisinvention is applicable to any patient who, when the treatment is tobegin, has no medical illnesses that would make treatment with acompound that modulates the expression of certain GABA_(A) receptorsubunits, such as flumazenil hazardous or is taking medicationcontraindicated with a compound that modulates the expression of certainGABA_(A) receptor subunits.

In general, the method of treatment of substance abuse provided by thisinvention begins with a complete medical and psychological examination,as described in detail above. Before, during, and after administrationof flumazenil, the symptoms of substance abuse withdrawal, heart rate,and blood pressure are monitored.

In one embodiment, a compound that modulates the expression of certainGABA_(A) receptor subunits, such as flumazenil, is administered untilqualitative and quantitative parameters indicative of substance abuseare lowered to acceptable ranges.

In one embodiment, a compound that modulates the expression of certainGABA_(A) receptor subunits, such as flumazenil, is administered at thelatter of a) when the patient starts to feel anxious (this is whenreceptors are “unmasked” as progesterone is substantially no longerconverted to allopregnanolone) or b) when it is safe to administer basedupon prior drugs given to the patient.

In one embodiment, a compound that modulates the expression of certainGABA_(A) receptor subunits, such as flumazenil, is administered at anyrate, provided that the rate is not detrimental to the patient, asdetermined by patient self-report of symptoms, or physiologicalparameters such as heart rate, heart rhythm, or blood pressure.

d. Additional Treatment Options

In some cases, in may be necessary to use, either during orpost-treatment, the following optional components of the treatmentprotocol. The following optional components are exemplary and aredependent upon a variety of factors, including but not limited toresponsiveness of the patient to treatment and if there is an indicationof a sustained increase in 5-alpha reductase activity.

i. 5-Alpha Reductase Inhibitor

It may be necessary to continually treat a patient with a 5-alphareductase inhibitor if there is an indication of a sustained increase in5-alpha reductase activity. 5-alpha-reductase inhibitors have beendescribed in detail above and will not be repeated herein.

ii. Prolactin

In some cases, it may be necessary to treat a patient to resolveincreased production of prolactin, due to an increase of estrogen levelscaused by a decline in progesterone feedback. A sustained increase inthe levels of prolactin leads to impairment of dopamine functionality,characterized by a higher stimulus threshold for dopamine release.Exemplary drugs include dopamine agonists, such as bromocriptine andprescription amphetamines, such as Ritalin and Adderal.

e. Post-Treatment Phase of Protocol

After a patient successfully completes the treatment phase of themethodology of the present invention, each patient will be prescribed apost-treatment regimen to follow, which includes, but is not limited to,the administration of pharmaceutical compositions, outpatient therapy, adiet program, and an exercise regimen. The components of thepost-treatment phase of the methodology of the present invention aredescribed in greater detail below.

Before discharge from the hospital, one or more of the followingcompositions or drugs may be prescribed: gabapentin and fluoxetinehydrochloride. Preferably, the compositions or drugs can be administeredin oral form to enable greater patient compliance and convenience. Itshould be appreciated that, to the extent any of drugs described hereinare not available in the jurisdiction in which this invention is beingpracticed equivalent functioning drugs may be used.

Psychotherapy/behavioral therapy and counseling may be critical for thesuccess of substance-dependency treatment when using pharmacologicaladjuncts. Thus, the methodology also provides for a maintenance programthat includes medications and incentives for the patient to continuewith their recovery process through continuing care programs. Due to thecomplexity of substance dependence, patients benefit most from acombination of pharmacologic and behavioral interventions.

As part of the treatment program, patients may optionally be instructedto attend the outpatient treatment center for several months withdecreasing frequency [i.e., once a week for the first three months, onceevery two weeks during the second three months, and once a month duringthe third three months].

Likewise, a semi-structured follow-up of cognitive behavior therapy isoptionally implemented. Individual and family psychotherapy is focusedon a plurality of interventions, including cognitive restructuring, worktherapy, prevention of relapse, and stress reduction, aimed atrehabilitating the social, family, work, personal and leisure life ofthe patient.

Depending upon the results of the initial examination, a universal orpatient-specific diet plan may optionally be administered in conjunctionwith the methodology. Depending upon the results of the initialexamination, a universal or patient-specific exercise programs mayoptionally be administered in conjunction with the methodology.

The following examples will serve to further illustrate the presentinvention without, at the same time, however, constituting anylimitation thereof. On the contrary, it is to be clearly understood thatresort may be had to various embodiments, modifications and equivalentsthereof which, after reading the description herein, may suggestthemselves to those skilled in the art without departing from the spiritof the invention.

VII. Example 1 Protocol for the Treatment of Opioid Abuse

“Opioid” is a term used for the class of drugs with opium-like and/ormorphine-like pharmacological action. An opioid is any agent that bindsto opioid receptors, which are mainly found in the central nervoussystem and gastrointestinal tract. There are many types of opioids,including endogenous opioids produced in the body (endorphins,dynorphins, enkephalins); opium alkaloids found in the opium plant(morphine, codeine, thebaine); semi-synthetic opioid derivatives(heroin, oxycodone, hydrocodone, dihydrocodeine, hydromorphine,oxymorphone, nicomorphine); and wholly synthetic opioid derivatives(phenylheptylamines, phenylpiperidines, diphenylpropylamine derivatives,benzomorphan derivatives, oripavine derivatives, morphinan derivatives,loperimide, diphenoxylate). As used herein, the term “opiates” shallrefer to any compound that binds to opioid receptors, including naturalopium alkaloids, semi-synthetic opioids derived therefrom, and syntheticopioids that have a similar physiochemistry to natural opiates andgenerally metabolize to morphine. In a clinical setting, opioids areused as analgesics and for relieving chronic and/or severe pain andother disease symptoms. Some opioids, however, are abused or usedillegally for their euphoria-inducing properties when administeredintravenously or when smoked.

The present example incorporates the teachings of the general treatmentmethodology described above. The components of the pre-treatment phaseof the methodology of the present invention have been described ingreater detail above and will not be repeated herein.

a. Pre-Treatment/Patient Assessment Phase

As described above, prior to admittance into the treatment program ofthe present invention, each patient should undergo a pre-treatmentanalysis. The pre-treatment analysis may be used to determine whether apatient is an optimal candidate for the treatment methodology of thepresent invention. In addition, the pre-treatment process may beadministered to prepare a patient for admittance into the treatmentmethodology of the present invention.

b. Preparing a Patient for Treatment with the Protocol of the PresentInvention

i. Placing a Patient in a State of Withdrawal

A patient may be placed in a state of withdrawal by actively inhibitingthe upregulation of endogenous neurosteroids and/or causing thedownregulation of endogenous neurosteroids. As previously described,this treatment step may be achieved by a) avoiding stress-inducingactivities, b) avoiding neurosteroid production enhancing activities, c)avoiding heightened progesterone levels in a patient, d) activelymodulating a woman's progesterone levels, or e) actively modulating amale's or female's progesterone levels through the administration of aneurosteroid inhibitor.

i. Additional Pre-Treatments

Even if a patient is placed in a state of withdrawal, the patient mayoptionally be subjected to other pre-treatment protocols for thesubstance of addiction. An exemplary protocol is described below, andthus, it should be noted that the use of such protocol is exemplary andthe invention is not limited to such protocol.

1. Optional Opiate Agonist Administration

The following treatment protocol is adapted from the Center forSubstance Abuse Treatment, Medication-Assisted Treatment for OpioidAddiction in Opioid Treatment Programs. Treatment Improvement Protocol(TIP) Series 43. DHHS Publication No. (SMA) 05-4048. Rockville, Md.:Substance Abuse and Mental Health Services Administration, 2005, whichis herein incorporated by reference. A few details of the protocol aredescribed below, however, it should be understood by one of ordinaryskill in the art that the Treatment Improvement Protocol referencedabove should be consulted for details. Treatment Improvement Protocols(TIPs) are best-practice guidelines for the treatment of substance abusedisorders, provided as a service of SAMHSA's Center for Substance AbuseTreatment (CSAT).

In an optional first step, the opiate user is administered an opiateagonist that preferably has a longer half-life and is less potent thanthe drug to which the patient has an addiction. Preferably, themedicament is an opiate agonist, such as, but not limited tobuprenorphine or methadone, and creates a dependency in the patient on asubstance that is less addictive and self-titrating. In a preferredembodiment, the substance is titrated down to slowly wean the patientoff of its effects. Substitution to complete withdrawal, however, isvery difficult and some patients have emergence of opiate withdrawalsymptoms that may result in relapse to illicit opiate use. Thus, in theoptional first step, the opiate agonist is decreased to the minimum dosethat the patient can tolerate without relapse.

a. Methadone

Methadone [chemical name 6-(dimethylamino)-4,4-diphenyl-3-heptanone] isa synthetic opioid analgesic with low addiction potential. It ischemically unlike morphine or heroin, but acts on the opioid receptorsand produces many of the same effects. It is typically administeredorally or intravenously. Methadone is longer lasting than morphine-baseddrugs and has a typical half-life of 24 hours or more, permittingadministration only once a day in opioid detoxification and maintenancetreatment programs. A patient is typically slowly weaned off ofmethadone.

While tolerance, dependence and withdrawal symptoms may develop, theydevelop much slower and are less acutely severe than those of morphineand heroin. Closely related to methadone, a synthetic compoundlevo-alphacetylmethadol (LAMM) has a 48-72 hour duration of action andcan be administered less frequently. Both LAAM and methadone arecontrolled substances and can only be used on an inpatient basis.

b. Buprenorphine

Buprenorphine [chemical name(2S)-2-[(−)-(5R,6R,7R,14S)-9a-cyclopropylmethyl-4,5-epoxy-3-hydroxy-6-methoxy-6,14-ethanomorphinan-7-yl]-3,3-dimethylbutan-2-ol]is a partial opioid agonist at μ-opioid receptors on GABA neurons andalso an opioid antagonist. Buprenorphine is a thebaine derivative, andits analgesic effect is due to the agonism of the μ-opioid receptor. Itis also a κ antagonist. Naloxone can partially revert the effects ofbuprenorphine. It has a long effect of about 48 hours, due to its slowdissociation from the opioid receptors. Buprenorphine is administered ashydrochloride as either intramuscular or intravenous injection or assublingual tablets. It is not administered orally, due to highfirst-pass metabolism. Unlike methadone, buprenorphine can be used on anoutpatient basis, as it is not a controlled substance.

2. Optional Opiate Antagonist Administration

Once the patient has stabilized at a dose level that is as low aspossible, but not low enough to trigger cravings and withdrawal, anopioid antagonist is optionally administered, such as naloxone,naltrexone, or nalmefene. Opiate antagonist administration, serves toflush opioids from the user's system and places the user in aphysiological state capable of effectively receiving an administrationof compound from the class of compounds that modulates GABA_(A) receptorexpression for the purpose of alleviating cravings and other withdrawalsymptoms.

a. Naloxone

Naloxone [chemical name17-allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one] is a drug used tocounter the effects of overdosing on opioids such as heroin andmorphine. It is a thebaine derivative and has an extremely high affinityfor μ-opioid receptors. Naloxone is a μ-opioid receptor competitiveagonist, and its rapid blocking of these receptors often leads to rapidonset of withdrawal symptoms. As a competitive agonist, naloxonedisplaces a substantial portion of receptor-bound opioid molecules, thusresulting in a reversal of effects δ-opioid receptors. Naloxone isusually injected intravenously for fast action, showing signs ofreversal of respiratory depression and reversal of coma within 30seconds. It is a short-duration pharmaceutical, with a half-life ofapproximately 60-100 minutes. Its effects last about 45 minutes.

b. Naltrexone

Naltrexone [chemical name17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6-one] isstructurally similar to naloxone but has a slightly increased affinityfor K-opioid receptors over naloxone, can be administered orally, andhas a longer duration of action. In addition, naltrexone can beadministered in a sustained-release form via an injection. It is anopioid receptor antagonist used in the management of alcohol dependenceand opioid dependence. Naltrexone, and its active metabolite6-β-naltrexol are competitive antagonists at μ- and κ-opioid receptors,and to a lesser extent δ-opioid receptors. Because it reversibly blocksor attenuates the effects of opioids, naltrexone is used in themanagement of opioid dependence. Naltrexone is typically used for rapiddetoxification procedures. It has a longer duration that naloxone, witha single oral dose being able to block injected heroine effects for 48hours.

c. Nalmefene

Nalmefene [chemical name17-(cyclopropylmethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol,hydrochloride salt], an opioid antagonist, is the 6-methylene analogueof naltrexone. It is used to prevent or reverse the effects of opioidsand has no opioid agonist activity.

c. Administration of a Compound from the Class of Compounds thatModulates GABA_(a) Receptor Expression

Once the pre-treatment protocol has been adhered to and completed, apatient is administered a compound from the class of compounds thatmodulates GABA_(A) receptor expression, such as flumazenil, as describedabove in the general treatment methodology.

d. Additional Treatment Options

Once the treatment protocol has been administered, additional treatmentoptions may be administered, as described above in the general treatmentmethodology.

e. Post-Treatment Phase of Protocol

Once the treatment protocol has been administered, a post-treatmentprotocol is administered, as described above in the general treatmentmethodology.

f. Hypothetical Treatment Example 1

Male, 45 years old, has been using heroin for 8 years and, under DSM IVcriteria, after undergoing pre-treatment assessment, has been diagnosedas being addicted to heroin.

Patient Preparation Four weeks prior to scheduled treatment, he isinitiated on a scheduled finasteride administration of 5 mg per day.Three days prior to scheduled treatment, the finasteride administrationis terminated and the patient is instructed to not engage in anystress-inducing activities or ingest any substances that would likelyincrease neurosteroid production.

Day 1 of Treatment: Male patient is administered flumazenil, viainfusion, at an amount less than 15 mg/day. The patient's heart rate andblood pressure are monitored, along with the patient's own qualitativeassessment of his health, including, but not limited to, subjectivefeelings of anxiety. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Male patient is administered flumazenil, viainfusion, at a rate of at least 2.5 mg/day.

Day 3 of Treatment: Male patient is evaluated to determine if a thirdday of treatment is necessary. If he continues to report feelings ofanxiety or cravings, he is again administered flumazenil, via infusion,at a rate of at least 2.5 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

g. Hypothetical Treatment Example 2

Male, 45 years old, has been using heroin for 8 years and, under DSM IVcriteria, after undergoing pre-treatment assessment, has been diagnosedas being addicted to heroin.

Patient Preparation One week prior to scheduled treatment, male patientis subjected to a conventional protocol for the treatment of opiateaddiction, such as described above. In one embodiment, male patient isadministered opiate agonist buprenorphine in an amount therapeuticallyeffective to begin titrating the substance down in the patient. There isno pre-determined time period for administering buprenorphine to thepatient. When the patient is titrated to sufficiently low levels, thetreatment protocol of the present invention is started. In oneembodiment, a sufficiently low level of buprenorphine is 3 mg.

Day 1 of Treatment: Male patient's buprenorphine dosage is reduced by0.25 mg, and thus male patient is administered 2.75 mg of buprenorphine.In addition, male patient is administered, via infusion, flumazenil in atherapeutically effective quantity of flumazenil of at least 1.0 mg/day.The total dose and rate are modified by the responsible physician basedon an evaluation of the patient's heart rate, blood pressure, andsubjective reports.

Day 2 of Treatment: Male patient's buprenorphine dosage is again reducedby 0.25 mg, and thus male patient is administered 2.50 mg ofbuprenorphine. Male patient is administered flumazenil, via infusion, ata rate of at least 1.0 mg/day. The total dose and rate are modified bythe responsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 3 of Treatment: Male patient's buprenorphine dosage is again reducedby 0.25 mg, and thus male patient is administered 2.25 mg ofbuprenorphine. Male patient is again administered flumazenil, viainfusion, at a rate of at least 1.0 mg/day.

Maintenance Phase Until Next Treatment: If needed, male patient isadvised that he may take buprenorphine in the amount of no more that2.25 mg/day until the next treatment.

Day 21 of Treatment: Male patient's buprenorphine dosage is reduced byhalf, and thus male patient is administered 1.125 mg of buprenorphine.In addition, male patient is administered, via infusion, flumazenil in atherapeutically effective quantity of flumazenil of at least 1.0 mg/day.The total dose and rate are modified by the responsible physician basedon an evaluation of the patient's heart rate, blood pressure, andsubjective reports.

Day 22 of Treatment: Male patient's buprenorphine dosage is againreduced by half, and thus male patient is administered 0.50 mg ofbuprenorphine. In addition, male patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 23 of Treatment: Male patient is instructed to stop taking allmedications, including buprenorphine.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

h. Hypothetical Treatment Example 3

Male, 45 years old, has been using heroin for 8 years and, under DSM IVcriteria, after undergoing pre-treatment assessment, has been diagnosedas being addicted to heroin.

Patient Preparation One week prior to scheduled treatment, male patientis subjected to a conventional protocol for the treatment of opiateaddiction, such as described above. In one embodiment, male patient isadministered opiate agonist buprenorphine in an amount therapeuticallyeffective to begin titrating the substance down in the patient. There isno pre-determined time period for administering buprenorphine to thepatient. When the patient is titrated to sufficiently low levels, thetreatment protocol of the present invention is started. In oneembodiment, a sufficiently low level of buprenorphine is 4 mg.

Day 1 of Treatment: Male patient's buprenorphine dosage is reduced by 1mg, and thus male patient is administered 3 mg of buprenorphine. Inaddition, male patient is administered, via infusion, flumazenil in atherapeutically effective quantity of flumazenil of at least 1.0 mg/day.The total dose and rate are modified by the responsible physician basedon an evaluation of the patient's heart rate, blood pressure, andsubjective reports.

Day 2 of Treatment: Male patient's buprenorphine dosage is again reducedby 1 mg, and thus male patient is administered 2 mg of buprenorphine.Male patient is administered flumazenil, via infusion, at a rate of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 3 of Treatment: Male patient's buprenorphine dosage is again reducedby 1 mg, and thus male patient is administered 1 mg of buprenorphine.Male patient is again administered flumazenil, via infusion, at a rateof at least 1.0 mg/day.

Day 4 of Treatment: Male patient is instructed to stop taking allmedications, including buprenorphine.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

i. Hypothetical Treatment Example 4

Male, 45 years old, has been using heroin for 8 years and, under DSM IVcriteria, after undergoing pre-treatment assessment, has been diagnosedas being addicted to heroin.

Patient Preparation: Male patient is administered buprenorphine in thelowest possible dose that patient can tolerate with substantiallyminimal or no withdrawal symptoms, thus creating a dependency in thepatient on a substance that is less addictive and self-titrating. Forexample, but not limited to such example, male patient is “addicted” toan amount of heroin equivalent of 15 mg of buprenorphine.

Day 1 of Treatment: On Day 1 of treatment, patient is administered 14 mgof buprenorphine. In addition, male patient is administered, viainfusion, flumazenil in a therapeutically effective quantity offlumazenil of at least 1.0 mg/day. The total dose and rate are modifiedby the responsible physician based on an evaluation of the patient'sheart rate, blood pressure, and subjective reports.

Day 2 of Treatment: Male patient's buprenorphine dosage is reduced by 1mg, and thus male patient is administered 13 mg of buprenorphine. Malepatient is administered flumazenil, via infusion, at a rate of at least1.0 mg/day. The total dose and rate are modified by the responsiblephysician based on an evaluation of the patient's heart rate, bloodpressure, and subjective reports.

Days 3-14 of Treatment: Male patient's buprenorphine dosage is reducedby 1 mg/day. In addition, male patient is again administered flumazenil,each day, via infusion, at a rate of at least 1.0 mg/day.

Day 15 of Treatment: Male patient is instructed to stop taking allmedications, including buprenorphine.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

VIII. Example 2 Protocol for the Treatment of Benzodiazepine Abuse

Benzodiazepines are often used for short-term relief of severe,disabling anxiety or insomnia. Long-term use can be problematic due tothe development of tolerance and dependency. As described in detailabove, they act on the GABA receptor GABA_(A), the activation of whichdampens higher neuronal activity. Benzodiazepine use can result in avariety of side effects, including, but not limited to drowsiness,ataxia, confusion, vertigo, and impaired judgment. In addition,benzodiazepines induce physical dependence and are potentiallyaddictive. An abrupt discontinuation of substance use may result inconvulsions, confusion, psychosis, or effects similar to deliriumtremens. Onset of withdrawal syndrome may be delayed and ischaracterized by insomnia, anxiety, tremor, perspiration, loss ofappetite, and delusions. Typical treatments for benzodiazepine abusehave been based on cognitive-behavioral therapy, weaning a patient offof the drug, and, in some cases, administering a benzodiazepineantagonist to counteract the drug's effects. These methods, however,fail in that they do not address the underlying physiochemical changesthat occur with addiction.

a. Pre-Treatment/Patient Assessment Phase

As described above, prior to admittance into the treatment program ofthe present invention, each patient should undergo a pre-treatmentanalysis. The pre-treatment analysis may be used to determine whether apatient is an optimal candidate for the treatment methodology of thepresent invention. In addition, the pretreatment process may beadministered to prepare a patient for admittance into the treatmentmethodology of the present invention.

b. Preparing a Patient for Treatment with the Protocol of the PresentInvention

i. Placing a Patient in a State of Withdrawal

A patient may be placed in a state of withdrawal by actively inhibitingthe upregulation of endogenous neurosteroids and/or causing thedownregulation of endogenous neurosteroids. As previously described,this treatment step may be achieved by a) avoiding stress-inducingactivities, b) avoiding neurosteroid production enhancing activities, c)avoiding heightened progesterone levels in a patient, d) activelymodulating a woman's progesterone levels, or e) actively modulating amale's or female's progesterone levels through the administration of aneurosteroid inhibitor.

ii. Additional Pre-Treatments

In one pre-treatment approach, a patient is gradually withdrawn througha gradual reduction of the dose. In one embodiment, a patient isinitiated on an administration of diazepam (Valium), 15 to 25 mg fourtimes daily. Sufficient diazepam is administered to suppress signs ofincreased withdrawal (e.g., increased pulse, increased blood pressure,or increased perspiration). Once a diazepam dose is reached whichsuppresses signs of withdrawal, administration may continue for 2additional days and then may be decreased by 10% per day. When thediazepam dose approaches 10% of the initial dose, the remaining dose isreduced slowly over 3 to 4 days and then discontinued. In this approach,benzodiazepine detoxification is accomplished in approximately 14 daysprior to the administration of a compound from the class of compoundsthat selectively modulates GABA_(A) expression. It should beappreciated, however, that longer detoxification may be required.

c. Administration of a Compound from the Class of Compounds thatModulates GABA_(a) Receptor Expression

Once the pretreatment protocol has been adhered to and completed, apatient is administered a compound from the class of compounds thatmodulates GABA_(A) receptor expression, such as flumazenil, as describedabove in the general treatment methodology.

d. Additional Treatment Options

Once the treatment protocol has been administered, additional treatmentoptions, as described above in the general treatment methodology, may beadministered.

e. Post-Treatment Phase of Protocol

Once the treatment protocol has been administered, a post-treatmentprotocol is administered, as described above in the general treatmentmethodology.

f. Hypothetical Treatment Example 1

Male, 25 years old, has been using alprazolam for 5 years and, under DSMIV criteria, after undergoing pre-treatment assessment, has beendiagnosed as being addicted to alprazolam.

Patient Preparation Four weeks prior to scheduled treatment, he isinitiated on a scheduled finasteride administration of 5 mg per day.Three days prior to scheduled treatment, the finasteride administrationis terminated and the patient is instructed to not engage in anystress-inducing activities or ingest any substances that would likelyincrease neurosteroid production.

Day 1 of Treatment: Male patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Male patient is administered flumazenil, viainfusion, at a rate of at least 1.0 mg/day. The total dose and rate aremodified by the responsible physician based on an evaluation of thepatient's heart rate, blood pressure, and subjective reports.

Day 3 of Treatment: Male patient is evaluated to determine if a thirdday of treatment is necessary. If he continues to report feelings ofanxiety or cravings, he is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

g. Hypothetical Treatment Example 2

Male, 35 years old, has been using alprazolam for 5 years and, underDSM-IV criteria, after undergoing pre-treatment assessment, has beendiagnosed as being addicted to alprazolam.

Patient Preparation Four weeks prior to scheduled treatment, he isinitiated on a scheduled finasteride administration of 5 mg per day.Three days prior to scheduled treatment, the finasteride administrationis terminated and the patient is instructed to not engage in anystress-inducing activities or ingest any substances that would likelyincrease neurosteroid production.

At least two weeks prior to treatment, patient then undergoes atreatment-induced benzodiazepine withdrawal process. In a preferredapproach, to prevent seizures and other problems, benzodiazepinewithdrawal is accomplished by gradual reduction of the dose. The patientis withdrawn using diazepam, 15 to 25 mg four times daily. The patientis administered sufficient additional diazepam to suppress signs ofincreased withdrawal (e.g., increased pulse, increased blood pressure,or increased perspiration). Once a diazepam dose is reached whichsuppresses signs of withdrawal, the diazepam administration is continuedfor 2 days and then is decreased by 10% per day. When the diazepam doseapproaches 10%, the dose is reduced slowly over 3 to 4 days and thendiscontinued.

Day 1 of Treatment: Male patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Male patient is administered flumazenil, viainfusion, at a rate of at least 1.0 mg/day. The total dose and rate aremodified by the responsible physician based on an evaluation of thepatient's heart rate, blood pressure, and subjective reports.

Day 3 of Treatment: Male patient is evaluated to determine if a thirdday of treatment is necessary. If he continues to report feelings ofanxiety or cravings, he is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

IX. Example 3 Protocol for the Treatment of Nicotine Abuse

Nicotine is a naturally occurring liquid alkaloid with strongstimulating effects. Nicotine readily diffuses through the skin, lungs,or mucous membranes and travels into blood vessels, the brain, and therest of a person's body. When inhaled, within 10 to 15 seconds, a personachieves the stimulatory effects of nicotine. The half-life of nicotineis about 60 minutes. Nicotine changes brain and body functions andinitially results in a rapid release of adrenaline, thereby causing arapid heartbeat, increased blood pressure, and rapid, shallow breathing.

Nicotine is a drug that induces both anxiolytic and anxiogenic effects,similar to those triggered by stressful events, contributing to emotionand reward. Through its interaction with nicotinic acetylcholinereceptors in the brain, which are located predominantly on pre-synapticterminals, nicotine modulates the release of many neurotransmitters,including serotonin, dopamine, noradrenaline, and GABA. Nicotine maydirectly or indirectly act on the GABA receptor GABA_(A), the activationof which dampens higher neuronal activity. Nicotine activates themesolimbic dopamine system, which is critical for the reinforcingproperties of the drug. Like heroin, cocaine, and alcohol, it issuggested that nicotine induces both a sense of well-being and physicaldependence and reduces stress-related anxiety in humans.

In addition, nicotine was demonstrated to increase the cerebrocorticalconcentrations of allopregnanolone and its precursors. Given thatallopregnanolone enhances GABA_(A) receptor function and plays animportant role in the regulation of anxiety and mood disorders, thetransient increase in the brain concentration of this endogenousneurosteroid triggered by nicotine may represent a homeostatic mechanismto reduce or counteract the neuronal excitability and anxiogenic-likeaction elicited by nicotine.

Given that allopregnanolone is among the most potent positive modulatorsof GABA_(A) receptors, which contribute to inhibitory regulation ofmesocortical and mesolimbic dopaminergic neurons, the nicotine-inducedincrease in the brain content of these hormones may facilitate theinhibition of these dopaminergic pathways induced by GABA.

Long-term use can be problematic due to the development of tolerance anddependency. An abrupt discontinuation of substance use may result inconvulsions, confusion, psychosis, or effects similar to deliriumtremens. Onset of withdrawal syndrome may be delayed and ischaracterized by insomnia, anxiety, tremor, perspiration, and loss ofappetite. Typical treatments for nicotine abuse have been based oncognitive-behavioral therapy and weaning a patient off of the drug.These methods, however, fail in that they do not address thephysiochemical changes that occur with addiction.

a. Pre-Treatment/Patient Assessment Phase

As described above, prior to admittance into the treatment program ofthe present invention, each patient should undergo a pre-treatmentanalysis. The pre-treatment analysis may be used to determine whether apatient is an optimal candidate for the treatment methodology of thepresent invention. In addition, the pre-treatment process may beadministered to prepare a patient for admittance into the treatmentmethodology of the present invention.

b. Preparing a Patient for Treatment with the Protocol of the PresentInvention

i. Placing a Patient in a State of Withdrawal

A patient may be placed in a state of withdrawal by actively inhibitingthe upregulation of endogenous neurosteroids and/or causing thedownregulation of endogenous neurosteroids. As previously described,this treatment step may be achieved by a) avoiding stress-inducingactivities, b) avoiding neurosteroid production enhancing activities, c)avoiding heightened progesterone levels in a patient, d) activelymodulating a woman's progesterone levels, or e) actively modulating amale's or female's progesterone levels through the administration of aneurosteroid inhibitor.

i. Other Pre-Treatment Approaches

The following clinical guidelines are adapted from guidelines publishedby the United States Department of Health and Human Services, and morespecifically, the Substance Abuse and Mental Health ServicesAdministration (hereinafter, SAMHSA), in Treating Tobacco Use andDependence, which is incorporated by reference. See Fiore M C, Bailey WC, Cohen S J, et al. Treating Tobacco Use and Dependence. ClinicalPractice Guideline. Rockville, Md.: U.S. Department of Health and HumanServices. Public Health Service. June 2000.

In one embodiment, a patient engages in counseling and behavioraltherapies, including, but not limited to, the provision of practicalcounseling (problem solving/skills training); the provision of socialsupport as part of treatment (intra-treatment social support); andassistance in securing social support outside of treatment(extra-treatment social support). In another embodiment, a patient isprescribed a pharmacotherapy that is known for increasing long-termsmoking abstinence rates: Bupropion SR, Nicotine gum, Nicotine inhaler,Nicotine nasal spray, Nicotine patch, Clonidine, and/or Nortriptyline.

It should be appreciated that, regardless of the particularpre-treatment therapy adopted, the patient should cease suchpharmacotherapies at least one week prior to the administration of acompound from the class of compounds that modulates GABA_(A) expression.

c. Administration of a Compound from the Class of Compounds thatModulates GABA_(a) Receptor Expression

Once the pre-treatment protocol has been adhered to and completed, apatient is administered a compound from the class of compounds thatmodulates GABA_(A) receptor expression, such as flumazenil, as describedabove in the general treatment methodology.

d. Additional Treatment Options

Once the treatment protocol has been administered, additional treatmentoptions, as described above in the general treatment methodology, may beadministered.

e. Post-Treatment Phase of Protocol

Once the treatment protocol has been administered, a post-treatmentprotocol is administered, as described above in the general treatmentmethodology.

f. Hypothetical Treatment Example 1

Female, 30 years old, has been using nicotine for 11 years and, isadmittedly addicted to nicotine. She has been taking oral contraceptivesfor at least five years.

Patient Preparation Treatment is scheduled during a time period in whichprogesterone is not administered (for example, in a 21 day pill pack,treatment is scheduled beginning with the first placebo day). If this isnot possible, female patient is instructed to withhold contraceptive usefor one week prior to scheduled treatment. Three days prior to scheduledtreatment, the patient is instructed to not engage in anystress-inducing activities or ingest any substances that would likelyincrease neurosteroid production (including oral contraceptives).

Day 1 of Treatment: Female patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Female patient is evaluated to determine if a secondday of treatment is necessary. If she continues to report feelings ofanxiety or cravings, she is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Day 3 of Treatment: Female patient is evaluated to determine if a thirdday of treatment is necessary. If she continues to report feelings ofanxiety or cravings, she is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Femalepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, she is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

g. Hypothetical Treatment Example 2

Female, 30 years old, has been using nicotine for 11 years and, isadmittedly addicted to nicotine.

Patient Preparation Six weeks prior to scheduled treatment, femalepatient is administered oral contraceptives. One week prior to scheduledtreatment, the administration of oral contraceptives is terminated. Twoweeks prior to treatment, female patient ceases any use of nicotine andis prescribed a nicotine patch for withdrawal symptoms. Thebenzodiazepine is given for up to four days at a dose of 5 mg tds. Threedays prior to scheduled treatment, the patient is instructed to notengage in any stress-inducing activities or ingest any substances thatwould likely increase neurosteroid production (including oralcontraceptives).

Day 1 of Treatment: Female patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Female patient is evaluated to determine if a secondday of treatment is necessary. If she continues to report feelings ofanxiety or cravings, she is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Day 3 of Treatment: Female patient is evaluated to determine if a thirdday of treatment is necessary. If she continues to report feelings ofanxiety or cravings, she is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Femalepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, she is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

X. Example 4 Protocol for the Treatment of Cannabis (THC) Abuse

Cannabis, or marijuana, is a plant containing THC(delta-9-tetrahydrocannabinol), a psychoactive chemical. When smoked,THC readily diffuses into an individual's lungs and, consequently, intohis bloodstream. THC changes brain and body functions and initiallyresults in a feeling of haziness and lightheadedness and deleteriouseffect on short-term memory, coordination, learning, andproblem-solving.

Long-term use can be problematic due to the development of tolerance anddependency. THC may directly or indirectly act on the GABA receptorGABA_(A), the activation of which dampens higher neuronal activity. THCuse can result in a variety of side effects, including, but not limitedto learning and memory problems, distorted perception, anxiety,paranoia, and panic attacks. In addition, THC induces physicaldependence and is addictive. Although not medically dangerous,withdrawal symptoms include anxiety, irritability, perspiration, sleepdisturbances, moodiness, and anorexia. Less common withdrawal symptomsinclude tremors, nausea and vomiting, occasional diarrhea, and excessivesalivation.

Typical treatments for THC abuse have been based on cognitive-behavioraltherapy and weaning a patient off of the drug. These methods, however,fail in that they do not address the physiochemical changes that occurwith addiction.

a. Pre-Treatment/Patient Assessment Phase

As described above, prior to admittance into the treatment program ofthe present invention, each patient should undergo a pre-treatmentanalysis. The pre-treatment analysis may be used to determine whether apatient is an optimal candidate for the treatment methodology of thepresent invention. In addition, the pre-treatment process may beadministered to prepare a patient for admittance into the treatmentmethodology of the present invention.

b. Preparing a Patient for Treatment with the Protocol of the PresentInvention

i. Placing a Patient in a State of Withdrawal

A patient may be placed in a state of withdrawal by actively inhibitingthe upregulation of endogenous neurosteroids and/or causing thedownregulation of endogenous neurosteroids. As previously described,this treatment step may be achieved by a) avoiding stress-inducingactivities, b) avoiding neurosteroid production enhancing activities, c)avoiding heightened progesterone levels in a patient, d) activelymodulating a woman's progesterone levels, or e) actively modulating amale's or female's progesterone levels through the administration of aneurosteroid inhibitor.

ii. Other Pre-Treatment Approaches

The following protocol is adapted from “Cannabis Dependence andTreatment”, GP Drug & Alcohol Supplement No. 10 (June 1998). In oneembodiment, a patient has been diagnosed with cannabis dependencebecause at least one of the following has been true for one month orlonger a) cannabis is often taken in larger amounts or over a longerperiod than the person intended, b) there is a persistent desire or oneor more unsuccessful efforts to cut down or control cannabis use, c) agreat deal of time is spent in activities necessary to get cannabis,e.g. theft, taking cannabis, or recovering from its effects, d) frequentintoxication or withdrawal symptoms occur when expected to fulfill majorrole obligations at work, school, or home, or when cannabis isphysically hazardous, e) there are important social occupational orrecreational activities given up or reduced because of cannabis use, f)cannabis use was continued despite knowledge of having a persistent orrecurrent social psychological or physical problem that is caused orexacerbated by the use of cannabis, and g) there is a marked tolerance

In one embodiment, a patient is prescribed a pre-treatment therapy basedupon a) what the patient wants; b) the severity of the patient'scannabis-related problems; c) the safety of the patient, i.e. the riskof suicide or harm to others from psychotic or depressive symptoms; andd) whether the patient is ready to quit. In one embodiment, thepre-treatment therapy comprises prescribing medicine to address symptomsof agitation, sleep disturbance, restlessness, and irritability. In oneembodiment, the medicine prescribed is a benzodiazepine (such asdiazepam), which may be given for up to four days at a dose of 5 mg tds.Benzodiazepines should not be continued beyond four days in thesepatients.

It should be appreciated that, regardless of the particular medicineprescribed adopted, the patient should cease all such pharmacotherapiesat least one week prior to the administration of a compound from theclass of compounds that modulates GABA_(A) receptor expression.

c. Administration of a Compound from the Class of Compounds thatModulates GABA_(a) Receptor Expression

Once the pre-treatment protocol has been adhered to and completed, apatient is administered a compound from the class of compounds thatmodulates GABA_(A) receptor expression, such as flumazenil, as describedabove in the general treatment methodology.

d. Additional Treatment Options

Once the treatment protocol has been administered, additional treatmentoptions, as described above in the general treatment methodology, may beadministered.

e. Post-Treatment Phase of Protocol

Once the treatment protocol has been administered, a post-treatmentprotocol is administered, as described above in the general treatmentmethodology.

f. Hypothetical Treatment Example 1

Female, 30 years old, has been using cannabis for 9 years and, underDSM-III-R criteria, has been diagnosed as being addicted to cannabis.She has been taking oral contraceptives for at least five years.

Patient Preparation One week prior to scheduled treatment, femalepatient withholds oral contraceptive administration. Three days prior toscheduled treatment, the patient is instructed to not engage in anystress-inducing activities or ingest any substances that would likelyincrease neurosteroid production (including oral contraceptives).

Day 1 of Treatment: Female patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Female patient is evaluated to determine if a secondday of treatment is necessary. If she continues to report feelings ofanxiety or cravings, she is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Day 3 of Treatment: Female patient is evaluated to determine if a thirdday of treatment is necessary. If she continues to report feelings ofanxiety or cravings, she is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Femalepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, she is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

g. Hypothetical Treatment Example 2

Female, 30 years old, has been using cannabis for 9 years and, underDSM-III-R criteria, has been diagnosed as being addicted to cannabis.

Patient Preparation Six weeks prior to scheduled treatment, femalepatient is administered oral contraceptives. One week prior to scheduledtreatment, the administration of oral contraceptives is terminated. Twoweeks prior to treatment, female patient ceases any use of cannabis andis prescribed a benzodiazepine for cannabis withdrawal symptoms. Thebenzodiazepine is given for up to four days at a dose of 5 mg tds. Threedays prior to scheduled treatment, the patient is instructed to notengage in any stress-inducing activities or ingest any substances thatwould likely increase neurosteroid production (including oralcontraceptives).

Day 1 of Treatment: Female patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Female patient is evaluated to determine if a secondday of treatment is necessary. If she continues to report feelings ofanxiety or cravings, she is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Day 3 of Treatment: Female patient is evaluated to determine if a thirdday of treatment is necessary. If she continues to report feelings ofanxiety or cravings, she is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Femalepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, she is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

XI. Example 5 Protocol for the Treatment of Caffeine Abuse

Caffeine, also known as trimethylxanthine, is a naturally occurringcardiac stimulant and mild diuretic. Caffeine induces nervousness andinsomnia in normal individuals, and it increases the level of anxiety inpatients prone to anxiety and panic attacks. As an anxiogenic, caffeinechanges brain and body functions and results in a rapid release ofadrenaline, thereby causing a rapid heartbeat, increased blood pressure,and rapid, shallow breathing.

Caffeine may directly or indirectly act on the GABA receptor GABA_(A),the activation of which dampens higher neuronal activity. In addition,it has been suggested that neuroactive steroids modulate the stimulantand anxiogenic effects of caffeine. More specifically, Concas et al.demonstrated that IP administration of caffeine resulted indose-dependent increases in the plasma and brain concentrations ofallopregnanolone as well as in those of its precursors pregnenolone andprogesterone. Thus, the effects of caffeine on the plasma and brainconcentrations of neuroactive steroids was shown to be similar to thoseof anxiogenic drugs, including those of direct and indirect inhibitorsof the GABA_(A) receptor complex that induce experimental anxiety inhumans. It was also demonstrated that these effects are antagonized bysystemic administration of anxiolytic drugs, further demonstrating thatboth pharmacologic treatments and experimental conditions that induceanxiety-like or conflict behavior also induces increases in the plasmaand brain concentrations of neuroactive steroids.

In addition, it is suggested that because caffeine induces bothneurotransmitter release and anxiety-like behavior associated withincreases in the plasma and brain concentrations of neuroactive steroidsthat the HPA axis might mediate such actions of caffeine. The transientincrease in the brain concentration of allopregnanolone triggered bycaffeine may reflect a physiological mechanism for reducing theactivation of the neuroendocrine and neurochemical pathways associatedwith the state of arousal and for limiting the extent of neuronalexcitability; consistent with the fact that neuroactive steroidsfunction to counteract overexcitation of the CNS.

Caffeine can induce physical dependence and is addictive, thus long-termuse can be problematic due to the development of tolerance anddependency. An abrupt discontinuation of substance use may result inanxiety and confusion. Typical treatments for caffeine dependence andabuse have been based on cognitive-behavioral therapy and weaning apatient off of the drug. These methods, however, fail in that they donot address the physiochemical changes that occur with addiction.

In further support of the effects of caffeine, Jain et al. demonstratedthat caffeine produced higher anxiety in animals previously treated withthe GABA_(A) receptor antagonist, bicuculline or either of the variousneurosteroid biosynthesis enzyme inhibitors viz. trilostane,finasteride, or indomethacin.

a. Pre-Treatment/Patient Assessment Phase

As described above, prior to admittance into the treatment program ofthe present invention, each patient should undergo a pre-treatmentanalysis. The pre-treatment analysis may be used to determine whether apatient is an optimal candidate for the treatment methodology of thepresent invention. In addition, the pre-treatment process may beadministered to prepare a patient for admittance into the treatmentmethodology of the present invention.

b. Preparing a Patient for Treatment with the Protocol of the PresentInvention

i. Placing a Patient in a State of Withdrawal

A patient may be placed in a state of withdrawal by actively inhibitingthe upregulation of endogenous neurosteroids and/or causing thedownregulation of endogenous neurosteroids. As previously described,this treatment step may be achieved by a) avoiding stress-inducingactivities, b) avoiding neurosteroid production enhancing activities, c)avoiding heightened progesterone levels in a patient, d) activelymodulating a woman's progesterone levels, or e) actively modulating amale's or female's progesterone levels through the administration of aneurosteroid inhibitor.

i. Other Pre-Treatment Approaches

Caffeine abuse and addiction should follow the basic principles oftreatment of substance dependence. These factors include: elimination ofthe offending substance(s); detoxification as required; medical andpsychiatric evaluation for associated conditions and complications;education about addiction, self-care, and recovery; relief of stress andthe development of a healthy lifestyle; and psychosocial treatment andsupport.

It should be appreciated that, regardless of the treatment approachadopted, the patient should cease all pharmacotherapies at least oneweek prior to the administration of a compound from the class ofcompounds that modulates GABA_(A) receptor expression.

c. Administration of a Compound from the Class of Compounds thatModulates GABA_(a) Receptor Expression

Once the pre-treatment protocol has been adhered to and completed, apatient is administered a compound from the class of compounds thatmodulates GABA_(A) receptor expression, such as flumazenil, as describedabove in the general treatment methodology.

d. Additional Treatment Options

Once the treatment protocol has been administered, additional treatmentoptions, as described above in the general treatment methodology, may beadministered.

e. Post-Treatment Phase of Protocol

Once the treatment protocol has been administered, a post-treatmentprotocol is administered, as described above in the general treatmentmethodology.

f. Hypothetical Treatment Example 1

Male, 40 years old, has been using caffeine for 15 years and, underDSM-IV criteria, has been diagnosed as being addicted to caffeine. Healso presents with acute headaches upon caffeine withdrawal.

Patient Preparation Four weeks prior to scheduled treatment, he isinitiated on a scheduled finasteride administration of 5 mg per day.Three days prior to scheduled treatment, the finasteride administrationis terminated and the patient is instructed to not engage in anystress-inducing activities or ingest any substances that would likelyincrease neurosteroid production.

Day 1 of Treatment: Male patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Male patient is evaluated to determine if a secondday of treatment is necessary. If he continues to report feelings ofanxiety or cravings, he is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Day 3 of Treatment: Male patient is evaluated to determine if a thirdday of treatment is necessary. If he continues to report feelings ofanxiety or cravings, he is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

XII. Example 6 Protocol for Treatment of Addiction to Non-BenzodiazepineAnxiolytics, Sedatives, Hypnotics, and Tranquilizers/Barbiturates (the“CNS Depressants”)

Non-benzodiazepine hypnotics are used for the short term treatment ofinsomnia (or difficulty in getting to sleep or staying asleep). Some,like chlormethiazole, can be used to help with agitation andrestlessness, and to help with alcohol withdrawal symptoms.

Barbiturates are drugs that act as central nervous system (CNS)depressant, producing a wide range of effects—from mild sedation toanesthesia. Today, barbiturates are infrequently used as anticonvulsantsand for the induction of anesthesia. Sometimes, two or more barbituratesare combined in a single tablet or capsule.

Barbiturates enhance the functioning of GABA and are general depressantsto nerve and muscle tissue. Mild to moderate barbiturate toxicity mimicsalcohol intoxication. Severe acute barbiturate toxicity results in CNSproblems, including lethargy and coma.

In moderate amounts, barbiturates produce a state of intoxication thatis similar to the effects of alcohol. Depending on the dose, frequency,and duration of use, one can rapidly develop tolerance, physicaldependence, and psychological dependence on barbiturates. As a userdevelops tolerance toward the barbiturate, the effective dose is closeto the lethal dose. In order to obtain the same level of intoxication,and thus gratification, the tolerant abuser will raise his dose to anear fatal or fatal level.

Nonbenzodiazepine sedatives such as intermediate- or short-actingbarbiturates or glutethimide are more likely than benzodiazepines toproduce lethal overdose because people who abuse them develop tolerancefor their sedative and euphoric effects but not for theirrespiratory-depressant effects. Therefore, as these people increasetheir dosages to get high, they suddenly can overdose to respiratorydepression. People who are opioid addicted and abuse nonbenzodiazepinesedatives usually need inpatient detoxification before starting MAT ormay do better with referral to a long-term, residential program such asa therapeutic community. Nonbenzodiazepine sedatives induce cytochromeP450 3A, an enzyme involved in methadone, levo-alpha acetyl methadol(LAAM), and buprenorphine metabolism, and can make stabilizationdifficult.

a. Pre-Treatment/Patient Assessment Phase

As described above, prior to admittance into the treatment program ofthe present invention, each patient should undergo a pre-treatmentanalysis. The pre-treatment analysis may be used to determine whether apatient is an optimal candidate for the treatment methodology of thepresent invention. In addition, the pre-treatment process may beadministered to prepare a patient for admittance into the treatmentmethodology of the present invention.

b. Preparing a Patient for Treatment with the Protocol of the PresentInvention

i. Placing a Patient in a State of Withdrawal

A patient may be placed in a state of withdrawal by actively inhibitingthe upregulation of endogenous neurosteroids and/or causing thedownregulation of endogenous neurosteroids. As previously described,this treatment step may be achieved by a) avoiding stress-inducingactivities, b) avoiding neurosteroid production enhancing activities, c)avoiding heightened progesterone levels in a patient, d) activelymodulating a woman's progesterone levels, or e) actively modulating amale's or female's progesterone levels through the administration of aneurosteroid inhibitor.

i. Other Pre-Treatment Approaches

In one embodiment, at least two weeks prior to treatment with a compoundfrom the class of compounds that selectively modulates GABA_(A) receptorexpression, a patient is prevented from taking any CNS Depressant drugsand a benzodiazepine, such as diazepam, is prescribed at a dose of 15 to25 mg four times daily. Sufficient additional diazepam is administeredto suppress signs of increased withdrawal (e.g., increased pulse,increased blood pressure, or increased perspiration). Once a diazepamdose is reached which suppresses signs of withdrawal, it is continuedfor 2 more days and then decreased by 10% per day.

It should be appreciated that, regardless of the treatment approachadopted, the patient should cease all pharmacotherapies at least oneweek prior to the administration of a compound from the class ofcompounds that modulates GABA_(A) receptor expression.

c. Administration of a Compound from the Class of Compounds thatModulates GABA_(a) Receptor Expression

Once the pre-treatment protocol has been adhered to and completed, apatient is administered a compound from the class of compounds thatmodulates GABA_(A) receptor expression, such as flumazenil, as describedabove in the general treatment methodology.

d. Additional Treatment Options

Once the treatment protocol has been administered, additional treatmentoptions, as described above in the general treatment methodology, may beadministered.

e. Post-Treatment Phase of Protocol

Once the treatment protocol has been administered, a post-treatmentprotocol is administered, as described above in the general treatmentmethodology.

f. Hypothetical Treatment Example 1

Male, 32 years old, has been using zalpelon for 5 years and, under DSMIV criteria, has been diagnosed as being addicted to zalpelon.

Patient Preparation Four weeks prior to scheduled treatment, he isinitiated on a scheduled finasteride administration of 5 mg per day.Three days prior to scheduled treatment, the finasteride administrationis terminated and the patient is instructed to not engage in anystress-inducing activities or ingest any substances that would likelyincrease neurosteroid production.

Day 1 of Treatment: Male patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Male patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 3 of Treatment: Male patient is evaluated to determine if a thirdday of treatment is necessary. If he continues to report feelings ofanxiety or cravings, he is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

g. Hypothetical Treatment Example 2

Male, 32 years old, has been using zalpelon for 5 years and, under DSMIV criteria, has been diagnosed as being addicted to zalpelon.

Patient Preparation Four weeks prior to scheduled treatment, he isinitiated on a scheduled finasteride administration of 5 mg per day. Twoweeks prior to scheduled treatment, he is prevented from taking any CNSDepressant drugs and is prescribed diazepam at a dose of 15 to 25 mgfour times daily. Once the diazepam dose that suppresses signs ofwithdrawal is reached, it is continued for 2 more days and thendecreased by 10% per day. Three days prior to scheduled treatment, thefinasteride administration is terminated and the patient is instructedto not engage in any stress-inducing activities or ingest any substancesthat would likely increase neurosteroid production.

Day 1 of Treatment: Male patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Male patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 3 of Treatment: Male patient is evaluated to determine if a thirdday of treatment is necessary. If he continues to report feelings ofanxiety or cravings, he is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

XIII. Example 7 Protocol for the Treatment of Anti-Depression DrugWithdrawal

Clinical depression is a health condition with mental and physicalcomponents reaching criteria generally accepted by clinicians (describedin greater detail below). Physiological symptoms of depression may bedue to changes or imbalances of chemicals which transmit information inthe brain, called neurotransmitters. Many modern anti-depressant drugsattempt to increase levels of certain neurotransmitters, like serotonin.Further, it has been shown that progesterone and its effects on GABAhave been implicated in depression and anti-depressant dependence.Cessation of a CNS drug, such as selective serotonin reuptakeinhibitors, tricyclic antidepressants, and monoamine oxides inhibitors,may cause withdrawal, an increased total GABA_(A) receptor α₄ subunitsrelative to GABA_(A) receptor α₁ subunits, which in turn, causesanxiety.

Khemraj et al. demonstrated that allopregnanolone plays a role in theanticonvulsant action of fluoxetine, thus supporting the hypothesis thatmodulation of GABA_(A) receptors by neurosteroid metabolites mediatesthe anticonvulsant action of fluoxetine. In addition, Pinna et al.suggest that pharmacological profiles of fluoxetine and fluvoxamine arecorrelated with the ability of these drugs to increase the brain andcerebrospinal fluid content of allopregnanolone, a potent positivemodulator of GABA action at GABA_(A) receptors. This further supportsthat selective serotonin reuptake inhibitors may act via dual pathways,both regulating levels of free serotonin and increasing levels ofendogenous neurosteroid, leading to the “addictive” properties ofSSRI's.

By taking away the effect of SSRI's on allopregnanolone, it may bepossible to treat patients with higher doses of the drug to regulatelevels of serotonin, since it has been demonstrated that theallopregnanolone upregulation occurs at lower doses that serotoninregulation.

a. Pre-Treatment/Patient Assessment Phase

As described above, prior to admittance into the treatment program ofthe present invention, each patient should undergo a pre-treatmentanalysis. The pre-treatment analysis may be used to determine whether apatient is an optimal candidate for the treatment methodology of thepresent invention. In addition, the pre-treatment process may beadministered to prepare a patient for admittance into the treatmentmethodology of the present invention.

b. Preparing a Patient for Treatment with the Protocol of the PresentInvention

i. Placing a Patient in a State of Withdrawal

A patient may be placed in a state of withdrawal by actively inhibitingthe upregulation of endogenous neurosteroids and/or causing thedownregulation of endogenous neurosteroids. As previously described,this treatment step may be achieved by a) avoiding stress-inducingactivities, b) avoiding neurosteroid production enhancing activities, c)avoiding heightened progesterone levels in a patient, d) activelymodulating a woman's progesterone levels, or e) actively modulating amale's or female's progesterone levels through the administration of aneurosteroid inhibitor.

c. Administration of a Compound from the Class of Compounds thatModulates GABA_(a) Receptor Expression

Once the pre-treatment protocol has been adhered to and completed, apatient is administered a compound from the class of compounds thatmodulates GABA_(A) receptor expression, such as flumazenil, as describedabove in the general treatment methodology.

d. Additional Treatment Options

Once the treatment protocol has been administered, additional treatmentoptions, as described above in the general treatment methodology, may beadministered.

e. Post-Treatment Phase of Protocol

Once the treatment protocol has been administered, a post-treatmentprotocol is administered, as described above in the general treatmentmethodology.

f. Hypothetical Treatment Example 1

Male, 32 years old, has been using fluoxetine hydrochloride for 5 yearsand, experiences anxiogenic symptoms upon withdrawal, similar to thosesymptoms in the DMS-IV criteria for addiction.

Patient Preparation Four weeks prior to scheduled treatment, malepatient is initiated on a scheduled finasteride administration of 5 mgper day. Three days prior to scheduled treatment, the finasterideadministration is terminated and the patient is instructed to not engagein any stress-inducing activities or ingest any substances that wouldlikely increase neurosteroid production, including fluoxetinehydrochloride.

Day 1 of Treatment: Male patient is administered, via infusion,flumazenil in a therapeutically effective quantity of flumazenil of atleast 1.0 mg/day. The total dose and rate are modified by theresponsible physician based on an evaluation of the patient's heartrate, blood pressure, and subjective reports.

Day 2 of Treatment: Male patient is evaluated to determine if a secondday of treatment is necessary. If he continues to report feelings ofanxiety or cravings, he is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Day 3 of Treatment: Male patient is evaluated to determine if a thirdday of treatment is necessary. If he continues to report feelings ofanxiety or cravings, he is again administered flumazenil, via infusion,at a rate of at least 1.0 mg/day.

Post-Treatment: Post-completion of treatment phase, patient isprescribed a post-treatment regimen to follow, which includes, but isnot limited to, the administration of pharmaceutical compositions,outpatient therapy, a diet program, and an exercise regimen. Malepatient is instructed to attend the outpatient treatment center forseveral months with decreasing frequency [i.e., once a week for thefirst three months, once every two weeks during the second three months,and once a month during the third three months]. If feelings of anxietyreturn, he is scheduled to repeat at least one day, and up to threedays, of flumazenil treatment.

The above examples are merely illustrative of the many applications ofthe system of present invention. Although only a few embodiments of thepresent invention have been described herein, it should be understoodthat the present invention might be embodied in many other specificforms without departing from the spirit or scope of the invention.Therefore, the present examples and embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope of theappended claims. All patents, publications and abstracts cited above areincorporated herein by reference in their entirety.

TABLE 1 EXEMPLARY LISTING OF PHARMACOLOGICAL COMPOUNDS AND SUGGESTEDDOSAGES FOR USE WITH THE PRESENT INVENTION SECONDARY EXEMPLARY DRUG DRUGCLASS DRUG CLASS LISTING DOSAGE ANALGESICS OPIATES (PAINKILLERS)ALFENTANIL FOR USE DURING GENERAL ANESTHESIA ALFENTA (alfentanilSPONTANEOUSLY BREATHING/ASSISTED VENTILATION: hydrochloride) Inductionof Analgesia: 8-20 mcg/kg; Maintenance of Analgesia: 3-5 mcg/kg q 5-20min or 0.5 to 1 mcg/kg/min; Total dose: 8-40 mcg/kg ASSISTED ORCONTROLLED VENTILATION: Incremental Injection (to attenuate response tolaryngoscopy and intubation): Induction of Analgesia: 20-50 mcg/kg;Maintenance of Analgesia: 5-15 mcg/kg q 5-20 min; Total dose: Up to 75mcg/kg. Continuous Infusion: (To provide attenuation of response tointubation and incision): Infusion rates are variable and should betreated to the desired clinical effect. Induction of Analgesia: 50-75mcg/kg; Maintenance of Analgesia: 0.5 to 3 mcg/kg/min (Average rate 1 to1.5 mg/kg/min); Total dose: Dependent on duration of procedure.Anesthetic Induction: Induction of Analgesia: 130-245 mcg/kg;Maintenance of Analgesia: 0.5 to 1.5 mcg/kg/min or general anesthetic;Total dose: Dependent on duration of procedure. At these doses, truncalrigidity should be expected and a muscle relaxant should be utilized;Administer slowly (over 3 minutes); Concentration of inhalation agentsreduced by 30-50% for initial hour. MONITORED ANESTHESIA CARE (MAC) (Forsedated and responsive, spontaneously breathing patients): Induction ofM.C. 3-8 mcg/kg; Maintenance of M.C. 3-5 mcg/kg q 5-20 min or 0.25 to 1mcg/kg/min; Total dose: 3-40 mcg/kg BUPRENORPHINE Administeredsublingually as a single daily dose in the range of 12 to 16 mg/day.Buprenorphine is also delivered transdermally in 25, 50, and 75 mcg/hour. BUTORPHANOL This formulation of butorphanol is administered every3-4 hours either as a nasal spray or injected into the buttock or hipmuscle or into a vein. The FDA does not regulate Stadol ® in moststates. CODEINE (also METHYL Codeine and codeine-combo preparations areusually taken every 4-6 MORPHINE) hours. Adults: 15 to 60 mg every 4 to6 hours (usual adult dose, 30 mg). Children: 1 Year of Age and Older -0.5 mg/kg of b.d. weight or 15 mg/m2 of b.d. surface every 4 to 6 hours.200 mg (oral) of codeine is about equal to 30 mg (oral) of morphine.CODEINON See Hydrocodone for details. PROPOXYPHENE Acetaminophen(Tylenol) and propoxyphene. (DARVOCET) It is formulated as a tablettaken every 4 hours by mouth. DEXTROPROPOXYPHENE Oral analgesic potencyis one-half to one-third that of codeine, with 65 mg approximatelyequivalent to about 600 mg of aspirin. Dextropropoxyphene is prescribedfor relief of mild to moderate pain. HEROIN ILLICIT SUBSTANCE/NOAPPROVED DOSING (DIACETYLMORPHINE) DIHYDROCODEINE Dihydrocodeine isapproximately twice as potent as codeine; this is taken intoconsideration while dosing dihydrocodeine. Codeine Dosage: For thetreatment of mild pain to moderate pain: Adults: 15-60 mg PO (oral)every 4-6 hours. For the treatment of non- productive cough: Adults:10-20 mg PO (oral) every 4-6 hours. For the treatment of diarrhoea:Adults: 30 mg PO (oral) FENTANYL Route of administration: patch,injected, oral transmucosal. The patch is usually changed every 72 hoursor as directed by physician. Fentanyl (DURAGESIC ®) should ONLY be usedin patients who are already receiving opioid therapy, who havedemonstrated opioid tolerance, and who require a total daily dose atleast equivalent to DURAGESIC ® 25 mcg/h. Patients who are consideredopioid- tolerant are those who have been taking, for a week or longer,at least 60 mg of morphine daily, or at least 30 mg of oral oxycodonedaily, or at least 8 mg oral hydromorphone daily, or an equianalgesicdose of another opioid. HYDROCODONE Five mg of hydrocodone is equivalentto 30 mg of codeine when DIHYDROCODEINONE administered orally. Also, adose of 15 mg (1/4 gr) of hydrocodone is equivalent to 10 mg (1/6 gr) ofmorphine. The typical therapeutic dose of 5 to 10 mg ispharmacologically equivalent to 30 to 60 mg of oral codeine.HYDROMORPHONE Dilaudid ® is formulated as oral tablets and liquid,rectal suppository, intra-muscular (buttock or hip muscle) injection,and intravenous (I.V.) solution. Dosing is every 4-6 hours for the oralforms and every 6-8 hours for the suppository. An I.V. drip allows forcontinuous administration and around-the-clock pain relief. It can begiven intravenously, intramuscularly, rectally, or orally. LAAM Theinitial dose street addicts should be 20 to 40 mg. Each LevomethadylAcetate subsequent dose, administered at 48- or 72-hour intervals, maybe Hydrochloride, also known as adjusted in increments of 5 to 10 mguntil a pharmacokinetic and Levo-alpha-acetylmethadol or pharmacodynamicsteady-state is reached. Patients dependent on Levacetylmethadol (LAM)methadone may require higher initial doses. METHADONE It comes astablets, dispersible tablets, liquid, and liquid concentrate. Patientstake it every 3-4 hours for severe pain and every 6-8 hours for chronicpain. MORPHINE and NO APPROVED DOSING FOR PURE MORPHINE. SEE MORPHINONESALTS. MORPHINE SULFATE MS Contin ® comes in the form of tablets,capsules, liquid, and rectal suppository, which are taken every 4 hours.Long-acting tablets and capsules can be taken every 8-12 hours or 1-2per day, respectively. OPIUM (NATURAL) ILLEGAL - NO FDA RECOMMENDEDUSAGE OXYCODONE OxyContin ® comes in liquid and tablet forms taken every6 hours. Long-acting tablets are available to take every 12 hours.OXYMORPHONE Injection: Subcutaneous or intramuscular administration:initially 1 mg to 1.5 mg, repeated every 4 to 6 hours as needed.Intravenous: 0.5 mg initially. For analgesia during labor 0.5 mg to 1 mgintramuscularly is recommended. Rectal Suppositories: One suppository, 5mg, every 4 to 6 hours. PETHIDINE (MEPERIDINE) Adults: The usual dosageis 50 mg to 150 mg intramuscularly, subcutaneously, or orally, every 3or 4 hours as necessary. Children: The usual dosage is 0.5 mg/lb to 0.8mg/lb intramuscularly, subcutaneously, or orally up to the adult dose,every 3 or 4 hours as necessary. REMIFENTANIL During Induction ofAnesthesia: ULTIVA should be administered at an infusion rate of 0.5 to1 mcg/kg/min with a hypnotic or volatile agent for the induction ofanesthesia. If endotracheal intubation is to occur less than 8 minutesafter the start of the infusion of ULTIVA, then an initial dose of 1mcg/kg may be administered over 30 to 60 seconds. For exact dosing forinduction, maintenance and continuation of general anesthesia, includingspecial cases, please refer to FDA Documents. SUFENTANIL Not more than 3total doses. Each dose must be at least one hour apart. THEBAINEThebaine is not used therapeutically, but is converted into a variety ofcompounds including codeine, hydrocodone, hydromorphone, oxycodone,oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine andetorphine. It is controlled in Schedule II of the Controlled SubstancesAct as well as under international law. TRAMADOL Tramadol isapproximately 10% as potent as morphine, when given by the IV/IM route.Oral doses range from 50-400 mg daily, with up to 600 mg daily whengiven IV/IM. TETRA- MARINOL Marinol: widely available throughprescription. It comes in the HYRDOC form of a pill and is also beingstudied by researchers for suitability ANNIBINOL/ via other deliverymethods, such as an inhaler or patch. The active THC ingredient ofMarinol is synthetic THC, which has been found to THC and some relievethe nausea and vomiting associated with chemotherapy and other the lossof appetite associated with various other disease states. cannibinoids,have analgesic properties. THC - Herbal and Synthetic ILLICITSUBSTANCE - NO FDA-APPROVED DOSAGE KETAMINE Intravenous Route: Theinitial dose of ketamine administered intravenously may range from 1mg/kg to 4.5 mg/kg (0.5 to 2 mg/lb). The average amount required toproduce five to ten minutes of surgical anesthesia has been 2 mg/kg (1mg/lb). Intramuscular Route: The initial dose of ketamine administeredintramuscularly may range from 6.5 to 13 mg/kg (3 to 6 mg/lb). A dose of10 mg/kg (5 mg/lb) will usually produce 12 to 25 minutes of surgicalanesthesia. BARBITURATES ALLOBARBITAL MRTD (Maximum RecommendedTherapeutic Dose) - 3.33000 mg/kg- body weight (bw)/day based upon anaverage adult weighing 60 kg. AMOBARBITAL Defined Daily Dose - 0.1 g, Nodata available from FDA. APROBARBITAL MRTD (Maximum RecommendedTherapeutic Dose) - 2.67000 mg/kg- body weight (bw)/day based upon anaverage adult weighing 60 kg. For trouble in sleeping: Adults-40 to 160milligrams (mg) at bedtime. For daytime sedation: Adults-40 mg threetimes a day. BARBEXACLONE 100 mg of barbexaclone is equivalent to 60 mgof phenobarbital. BARBITAL MRTD (Maximum Recommended Therapeutic Dose)in mg/kg- (VERONAL) body weight (bw)/day based upon an average adultweighing 60 kg - 10.00000 BUTABARBITAL Butabarbital Oral is used totreat the following: Severe Anxiety, Additional Agent to Induce GeneralAnesthesia, Abnormal Trouble Sleeping MRTD (Maximum RecommendedTherapeutic Dose) in mg/kg- body weight (bw)/day based upon an averageadult weighing 60 kg - 2.000 BUTALBITAL MRTD (Maximum RecommendedTherapeutic Dose) in mg/kg- Butalbital, 5-allyl-5- body weight (bw)/daybased upon an average adult weighing isobutylbarbituric acid. 60 kg -5.000 COMMON COMBINATIONS INCLUDE: Butalbital and acetaminophenbutalbital, acetaminophen, and caffeine butalbital and aspirinbutalbital, aspirin, and caffeine BUTOBARBITAL 50 mg of Butobarbital isequivalent to 10 mg of Diazepam; Acc. to (SONERYL) Nordic Statistics onMedicines, the Defined Daily Dose of Butobarbital is 150 mg. No dataavailable from FDA. CYCLOBARBITAL MRTD (Maximum Recommended TherapeuticDose) in mg/kg- body weight (bw)/day based upon an average adultweighing 60 kg - 6.67000 ETHALLOBARBITAL N.A. HEPTABARBITAL DefinedDaily Dose - 0.2 g, No data available from FDA. HEXOBARBITAL MRTD(Maximum Recommended Therapeutic Dose) in mg/kg- body weight (bw)/daybased upon an average adult weighing 60 kg - 8.33000 MEPHOBARBITALEpilepsy: Average dose for adults: 400 mg to 600 mg daily; children(METHYLPHENOBARBITAL) under 5 years: 16 mg to 32 mg three or four timesdaily; children over 5 years: 32 mg to 64 mg three or four times daily.Sedation: Adults: 32 mg to 100 mg optimum dose, 50 mg three to fourtimes daily. Children: 16 mg to 32 mg three to four times daily.METHARBITAL METHOHEXITAL For induction of anesthesia, a 1% solution isadministered at a rate of about 1 mL/5 seconds. The dose required forinduction may range from 50 to 120 mg or more but averages about 70 mg.The usual dosage in adults ranges from 1 to 1.5 mg/kg. Maintenance ofanesthesia may be accomplished by intermittent injections of the 1%solution or, more easily, by continuous intravenous drip of a 0.2%solution. Intermittent injections of about 20 to 40 mg (2 to 4 mL of a1% solution) may be given as required, usually every 4 to 7 minutes. Forcontinuous drip, the average rate of administration is about 3 mL of a0.2% solution/minute (1 drop/second). PENTOBARBITAL The usual adultdosage of NEMBUTAL Sodium Solution is 150 to 200 mg as a single IMinjection; the recommended pediatric dosage ranges from 2 to 6 mg/kg asa single IM injection not to exceed 100 mg. The rate of IV injectionshould not exceed 50 mg/min for pentobarbital sodium. PHENOBARBITALPediatric Oral Dosage (as recommended by the American Academy ofPediatrics): Preoperative: 1 to 3 mg/kg. Adult Oral Dosage: Daytimesedative: 30 to 120 mg daily in 2 to 3 divided doses. Bedtime hypnotic:100 to 320 mg. Anticonvulsant: 50 to 100 mg 2 to 3 times daily.PRIMIDONE Adult Dosage: Patients 8 years of age and older who havereceived no previous treatment may be started on primidone according tothe following regimen using Primidone 250 mg tablets. Days 1-3: 100 to125 mg at bedtime; Days 4-6: 100 to 125 mg b.i.d.; Days 7-9: 100 to 125mg t.i.d.; Day 10-maintenance; 250 mg t.i.d. For most adults andchildren 8 years of age and over, the usual maintenance dosage is threeto four 250 mg primidone tablets daily in divided doses (250 mg t.i.d.or q.i.d.). If required, an increase to five or six 250 mg tablets dailymay be made but daily doses should not exceed 500 mg q.i.d. PediatricDosage: For children under 8 years of age, the following regimen may beused: Days 1-3: 50 mg at bedtime; Days 4-6: 50 mg b.i.d.; Days 7-9: 100mg b.i.d.; Day 10-maintenance: 125. mg t.i.d. to 250 mg t.i.d. Forchildren under 8 years of age, the usual maintenance dosage is 125 to250 mg three times daily, or 10-25 mg/kg/day in divided doses.SECOBARBITAL For oral dosage form (capsules): For trouble in sleeping:Adults-100 milligrams (mg) at bedtime. Children-Dose must be determinedby your doctor. For daytime sedation: Adults-30 to 50 mg three or fourtimes a day. Children-Dose is based on body weight or size and must bedetermined by your doctor. The usual dose is 2 mg per kilogram (kg) (0.9mg per pound) of body weight three times a day. For sedation beforesurgery: Adults-200 to 300 mg one or two hours before surgery.Children-Dose is based on body weight and must be determined by yourdoctor. The usual dose is 2 to 6 mg per kg (0.9 to 2.7 mg per pound) ofbody weight one or two hours before surgery. However, the dose isusually not more than 100 mg. For injection dosage form: For trouble insleeping: Adults-100 to 200 mg injected into a muscle, or 50 to 250 mginjected into a vein. Children-Dose is based on body weight or size andmust be determined by your doctor. The usual dose is 3 to 5 mg per kg(1.4 to 2.3 mg per pound) of body weight, injected into a muscle.However, the dose is usually not more than 100 mg. For sedation beforedental procedures: Adults-Dose is based on body weight and must bedetermined by your doctor. The usual dose is 1.1 to 2.2 mg per kg (0.5to 1 mg per pound) of body weight, injected into a muscle ten to fifteenminutes before the procedure. Children-Dose must be determined by yourdentist. For sedation before a nerve block: Adults-100 to 150 mg,injected into a vein. For sedation before surgery: Children-Dose isbased on body weight and must be determined by your doctor. The usualdose is 4 to 5 mg per kg (1.8 to 2.3 mg per pound) of body weight,injected into a muscle. TALBUTAL MRTD (Maximum Recommended TherapeuticDose) in mg/kg- (Lotusate ®), also called 5-allyl- body weight (bw)/daybased upon an average adult weighing 5-sec-butylbarbituric acid. 60 kg -3.30000 THIOBARBITAL N.A. THIOPENTAL Use in Anesthesia: Moderately slowinduction can usually be Pentothal (Thiopental Sodium accomplished inthe “average” adult by injection of 50 to 75 mg for Injection, USP). (2to 3 mL of a 2.5% solution) at intervals of 20 to 40 seconds, dependingon the reaction of the patient. Once anesthesia is established,additional injections of 25 to 50 mg can be given whenever the patientmoves. Use in Convulsive States: For the control of convulsive statesfollowing anesthesia (inhalation or local) or other causes, 75 to 125 mg(3 to 5 mL of a 2.5% solution) should be given as soon as possible afterthe convulsion begins. Convulsions following the use of a localanesthetic may require 125 to 250 mg of Pentothal given over a tenminute period. Use in Psychiatric Disorders: For narcoanalysis andnarcosynthesis in psychiatric disorders, premedication with ananticholinergic agent may precede administration of Pentothal. After atest dose, Pentothal (Thiopental Sodium for Injection, USP) is injectedat a slow rate of 100 mg/mm (4 mL/min of a 2.5% solution) with thepatient counting backwards from 100. Shortly after counting becomesconfused but before actual sleep is produced, the injection isdiscontinued. Allow the patient to return to a semidrowsy state whereconversation is coherent. Alternatively, Pentothal may be administeredby rapid I.V. drip using a 0.2% concentration in 5% dextrose and water.At this concentration, the rate of administration should not exceed 50mL/min. VINBARBITAL MRTD (Maximum Recommended Therapeutic Dose) inmg/kg- Vinbarbital (5-Ethyl-5-(1- body weight (bw)/day based upon anaverage adult weighing methyl-1-butenyl)barbituric 60 kg - 3.33000acid). VINYLBITAL Defined Daily Dose - 0.15 g, No data available fromFDA. Butylvinyl BENZODIAZEPINES ALPRAZOLAM Dosage Depends on Disorder:Oral (For anxiety or nervous tension): Start: 0.25 mg to 0.5 mg 3 timesdaily. Maximum: 4 mg in 24 hours. Oral (For panic disorder): Start: 0.5mg 3 times daily. Increases: 1 mg daily in 3 to 4 day intervals.Maximum: 10 mg in 24 hours. BROMAZEPAM Not commercially available in theU.S. BROTIZOLAM Brotizolam is not approved for sale in the United Statesor Canada. CAMAZEPAM Defined Daily Dose - 30 mg, No data available fromFDA. CHLORDIAZEPOXIDE For relief of mild and moderate anxiety disordersand symptoms of anxiety: 5 mg or 10 mg, 3 or 4 times daily. For reliefof server anxiety disorders and symptoms of anxiety: 20 mg or 25 mg, 3or 4 times daily. Geriatric patients or in the presence of debilitatingdisease: 5 mg, 2 to 4 times daily. CLONAZEPAM Seizure Disorders: Adults:The initial dose for adults with seizure disorders should not exceed 1.5mg/day divided into three doses. Dosage may be increased in incrementsof 0.5 to 1 mg every 3 days until seizures are adequately controlled oruntil side effects preclude any further increase. Maintenance dosagemust be individualized for each patient depending upon response. Maximumrecommended daily dose is 20 mg. Pediatric Patients: Klonopin isadministered orally. In order to minimize drowsiness, the initial dosefor infants and children (up to 10 years of age or 30 kg of body weight)should be between 0.01 and 0.03 mg/kg/day but not to exceed 0.05mg/kg/day given in two or three divided doses. Dosage should beincreased by no more than 0.25 to 0.5 mg every third day until a dailymaintenance dose of 0.1 to 0.2 mg/kg of body weight has been reached,unless seizures are controlled or side effects preclude furtherincrease. Whenever possible, the daily dose should be divided into threeequal doses. If doses are not equally divided, the largest dose shouldbe given before retiring. Panic Disorder: Adults: The initial dose foradults with panic disorder is 0.25 mg bid. An increase to the targetdose for most patients of 1 mg/day may be made after 3 days. Therecommended dose of 1 mg/day is based on the results from a fixed dosestudy in which the optimal effect was seen at 1 mg/day. Higher doses of2, 3 and 4 mg/day in that study were less effective than the 1 mg/daydose and were associated with more adverse effects. Nevertheless, it ispossible that some individual patients may benefit from doses of up to amaximum dose of 4 mg/day, and in those instances, the dose may beincreased in increments of 0.125 to 0.25 mg bid every 3 days until panicdisorder is controlled or until side effects make further increasesundesired. To reduce the inconvenience of somnolence, administration ofone dose at bedtime may be desirable. Treatment should be discontinuedgradually, with a decrease of 0.125 mg bid every 3 days, until the drugis completely withdrawn. CLOTIAZEPAM Clotiazepam is not approved forsale in the United States or Canada CLORAZEPATE ORAL: START: 15 mg/dailyINCREASES: As needed. MAXIMUM: 60 mg in 24 hours CLOXAZOLAM Cloxazolamis not approved for sale in the United States or Canada. DELORAZEPAMDefined Daily Dose - 3 mg, No data available from FDA. DIAZEPAMManagement of Anxiety Disorders and Relief of Symptoms of Anxiety:Depending upon severity of symptoms - 2 mg to 10 mg, 2 to 4 times daily.Symptomatic Relief in Acute Alcohol Withdrawal: 10 mg, 3 or 4 timesduring the first 24 hours, reducing to 5 mg, 3 or 4 times daily asneeded. Adjunctively for Relief of Skeletal Muscle Spasm: 2 mg to 10 mg,3 or 4 times daily. Adjunctively in Convulsive Disorders. 2 mg to 10 mg,2 to 4 times daily. Geriatric Patients, or in the presence ofdebilitating disease: 2 mg to 2.5 mg, 1 or 2 times daily initially;increase gradually as needed and tolerated. Pediatric patients: Becauseof varied responses to CNS-acting drugs, initiate therapy with lowestdose and increase as required. Not for use in pediatric patients under 6months. 1 mg to 2.5 mg, 3 or 4 times daily initially; increase graduallyas needed and tolerated. ESTAZOLAM The recommended initial dose foradults is 1 mg at bedtime; however, some patients may need a 2 mg dose.In healthy elderly patients, 1 mg is also the appropriate starting dose,but increases should be initiated with particular care. In small ordebilitated older patients, a starting dose of 0.5 mg, while onlymarginally effective in the overall elderly population, should beconsidered. ETIZOLAM Etizolam is not approved for sale in the UnitedStates or Canada. FLUDIAZEPAM Defined Daily Dose - 0.75 mg, No dataavailable from FDA. FLUNITRAZEPAM Flunitrazepam has not been approved bythe Food and Drug Administration for medical use in the United States.It is available only by private prescription in the United KingdomFLURAZEPAM Dosage should be individualized for maximal beneficialeffects. The usual adult dosage is 30 mg before retiring. In somepatients, 15 mg may suffice. In elderly and/or debilitated patients, 15mg is usually sufficient for a therapeutic response HALAZEPAM For oraldosage form (tablets): For anxiety: Adults-20 to 40 milligrams (mg)three or four times a day. Children younger than 18 years of age-Use anddose must be determined by your doctor. Older adults-20 mg one or twotimes a day. HALOXAZOLAM Defined Daily Dose - 7.50 mg, No data availablefrom FDA. LOPRAZOLAM It is available in 1 mg tablets. The usual adultdose is 1-2 mg at bedtime, the higher dose being recommended forpatients who have previously been treated with benzodiazepines forsevere persistent insomnia. An initial dose of 0.5 mg-1.0 mg isrecommended in elderly and debilitated patients. LOREZEPAM The usualrange is 2 to 6 mg/day given in divided doses, the largest dose beingtaken before bedtime, but the daily dosage may vary from 1 to 10 mg/day.For anxiety, most patients require an initial dose of 2 to 3 mg/daygiven b.i.d. or t.i.d. For insomnia due to anxiety or transientsituational stress, a single daily dose of 2 to 4 mg may be given,usually at bedtime. For elderly or debilitated patients, an initialdosage of 1 to 2 mg/day in divided doses is recommended, to be adjustedas needed and tolerated. MEDAZEPAM Defined daily dose as used in theNordic Statistics on Medicines - 20 mg; No data available from FDA.MIDAZOLAM For preoperative sedation/anxiolysis/amnesia. Intramuscular -The recommended premedication dose of VERSED for good risk (ASA PhysicalStatus I & II) adult patients below the age of 60 years is 0.07 to 0.08mg/kg IM (approximately 5 mg IM) administered up to 1 hour beforesurgery. The dose must be individualized and reduced when IM VERSED isadministered to patients with chronic obstructive pulmonary disease,other higher risk surgical patients, patients 60 or more years of age,and patients who have received concomitant narcotics or other CNSdepressants. In a study of patients 60 years or older, who did notreceive concomitant administration of narcotics, 2 to 3 mg (0.02 to 0.05mg/kg) of VERSED produced adequate sedation during the preoperativeperiod. The dose of 1 mg IM VERSED may suffice for some older patientsif the anticipated intensity and duration of sedation is less critical.Intravenous - VERSED 1 mg/mL formulation is recommended forsedation/anxiolysis/amnesia for procedures to facilitate slowerinjection. Both the 1 mg/mL and the 5 mg/mL formulations may be dilutedwith 0.9% sodium chloride or 5% dextrose in water. 1. Healthy AdultsBelow the Age of 60: Titrate slowly to the desired effect (eg, theinitiation of slurred speech). Some patients may respond to as little as1 mg. No more than 2.5 mg should be given over a period of at least 2minutes. A total dose greater than 5 mg is not usually necessary toreach the desired endpoint. If narcotic premedication or other CNSdepressants are used, patients will require approximately 30% lessVERSED than unpremedicated patients. 2. Patients Age 60 or Older, andDebilitated or Chronically Ill Patients: Titrate slowly to the desiredeffect (eg, the initiation of slurred speech). Some patients may respondto as little as 1 mg. No more than 1.5 mg should be given over a periodof no less than 2 minutes. If additional titration is necessary, itshould be given at a rate of no more than 1 mg over a period of 2minutes, waiting an additional 2 or more minutes each time to fullyevaluate the sedative effect. Total doses greater than 3.5 mg are notusually necessary. Epileptic fit: 10 mg intranasally or as buccal.NIMETAZEPAN MRTD (Maximum Recommended Therapeutic Dose) in mg/kg- bodyweight (bw)/day based upon an average adult weighing 60 kg - 0.08330NITRAZEPAM Nitrazepam shortens the time required to fall asleep andlengthens the duration of this sleep. Typically, it may work within anhour and allow the individual to maintain sleep for 4 to 6 hours. It isno longer available in the United States. NORDAZEPAM Defined DailyDose - 15 mg, No data available from FDA. OXAZEPAM Mild to moderateanxiety, with associated tension, irritability, agitation or relatedsymptoms of functional origin or secondary to organic disease: 10 to 15mg, 3 or 4 times daily. Severe anxiety syndromes, agitation, or anxietyassociated with depression: 15 to 30 mg, 3 or 4 times daily. Olderpatients with anxiety, tension, irritability, and agitation: Initialdosage - 10 mg, 3 times daily. If necessary, increase cautiously to 15mg, 3 or 4 times daily. Alcoholics with acute inebriation,tremulousness, or anxiety on withdrawal: 15 to 30 mg, 3 or 4 timesdaily. OXAZOLAM 20 mg is equivalent to 10 mg of Diazepam. MRTD (MaximumRecommended Therapeutic Dose) in mg/kg- body weight (bw)/day based uponan average adult weighing 60 kg - 1.0000 PINAZEPAM MRTD (MaximumRecommended Therapeutic Dose) in mg/kg- body weight (bw)/day based uponan average adult weighing 60 kg - 0.33300 PRAZEPAM MRTD (MaximumRecommended Therapeutic Dose) in mg/kg- body weight (bw)/day based uponan average adult weighing 60 kg - 1.00000 QUAZEPAM The recommendedinitial dose is 15 milligrams daily. Your doctor may later reduce thisdosage to 7.5 milligrams. TEMAZEPAM While the recommended usual adultdose is 15 mg before retiring, 7.5 mg may be sufficient for somepatients, and others may need 30 mg. In transient insomnia, a 7.5 mgdose may be sufficient to improve sleep latency. In elderly and/ordebilitated patients it is recommended that therapy be initiated with7.5 mg until individual responses are determined. TETRAZEPAM DefinedDaily Dose - 100 mg, No data available from FDA. TOFISOPAM Tofisopam isnot approved for sale in the US or Canada. However, Vela Pharmaceuticalsof New Jersey is developing the D- enantiomer (dextofisopam) as atreatment for IBS. TRIAZOLAM The recommended dose for most adults is0.25 mg before retiring. A dose of 0.125 mg may be found to besufficient for some patients (e.g., low body weight). A dose of 0.5 mgshould be used only for exceptional patients who do not respondadequately to a trial of a lower dose since the risk of several adversereactions increases with the size of the dose administered. A dose of0.5 mg should not be exceeded. In geriatric and/or debilitated patientsthe recommended dosage range is 0.125 mg to 0.25 mg. Therapy should beinitiated at 0.125 mg in this group and the 0.25 mg dose should be usedonly for exceptional patients who do not respond to a trial of the lowerdose. A dose of 0.25 mg should not be exceeded in these patients.HORMONES/ ESTROGENS See other columns. Hormone-Containing ContraceptivesGeneral Dosing Information: CONTRACEPTIVES include: ethinyl Combinationcontraceptives are those containing both estrogen and estradiol andprogesterone. mestranol. Several types of combination birth controlpills exist, including PRO- monophasic pills, biphasic pills, triphasicpils, and 91-day cycle GESTERONES pills. include: USE: Starting at thebeginning of the pill pack, take one each day at Norethynodrel,approximately the same time every day to increase efficacy.norethindrone, WHEN TO BEGIN: The following regimens may be used whennorethindrone first starting on birth control pills: acetate, Taking onepill each day, starting on the fifth day after the norgestimate, onsetof menses and continuing for 21 or 28 days. desogestrel, Beginning pillson the first day of the menstrual period. ethyndiol Beginning on thefirst Sunday after the menstrual period diacetate, starts. norgestrel,21-DAY PILL CONTAINER: Take one pill daily for 21 days, stoplevonorgestrel, for 7 days, then resume taking the pills with a newcontainer of pills. drospirenone. 28-DAY PILL CONTAINER: Start with thefirst pill in the container and swallow one daily for 28 days. Do notstop taking the pills. The last 7 ae usually placebos. 91-DAY PILLCONTAINER: One pill is taken daily for 12 weeks, followed by one week ofinactive pills. A menstrual period occurs during the week of inactivepills, so women on this regimen have a period only once every threemonths. Monophasic Pills: Alesse, Brevicon, Demulen, Desogen, Levlen,Levlite, Loestrin, Microgestin, Modicon, Necon, Nelova, Nordette,Norinyl, Ortho-Cept, Ortho-Cyclen, Ortho-Novum, Ovcon, Ovral, Yasmin,Zovia. Monophasic pills have a constant dose of estrogen and progestinin each of the hormonally active pills through the entire cycle (21 daysof ingesting active pills). Several of the brands listed above may beavailable in several strengths of estrogen or progesterone, from whichdoctors choose according to a woman's individual needs. Biphasic Pills:Jenest, Mircette, Necon 10/11, Nelova 10/11, and Ortho-Novum 10/11Biphasic Pills typically contain two different progesterone doses. Theprogesterone dose is increased about halfway through the cycle.Triphasic Pills: Cyclessa, Estrostep, Ortho-Novum 7/7/7, Ortho Tri-Cyclen, Ortho Tri-Cyclen LO, Tri-Levlen, Tri-Norinyl, Triphasil, TrivoraTriphasic pills gradually increase the dose of estrogen during the cycle(some pills also increase the progesterone dose). Three differentincreasing pill doses are contained in each cycle. Ninety-One Day BCP:Levonorgestrel/ethynl estradiol (Seasonale) These pills are monophasicbirth control pills that have been approved for use on a daily basis for84 days without interruption. Users have fewer schedules menstrualcycles (only 1 period every 3 months). Topical Contraceptive Patch:Norelgestromin/ethinyl estradiol (Ortho Evra) A new patch is applied onthe same day of the week, each week for three weeks in a row. The firstpatch is applied on either the first day of the menstrual period or onthe Sunday following menses. On the fourth week, no patch is applied.Another 4-week cycle is started by applying a new patch following the7-day patch free period. Long-Acting, Injectable, Progesterone-OnlyContraceptives: Medroxyprogesterone acetate (Depo-Provera) The firstinjection is given within five days following the onset of menstruation.After that, an injection is needed every 11-13 weeks. Unlike pills, theinjection works right away. Progesterone-Only Pills: Norethindrone(Nor-QD) Progesterone-only pills, also known as mini-pills, are not usedwidely in the US. POPs are ingested once daily, every day. They may bestarted on any day, and there are no pill-free days or different coloredpills to track. Since progesterone is the only hormonal ingredient,estrogen-related side effects are avoided. Vaginal Ring:Etonogestrel/ethinyl estradiol (NuvaRing) The ring is self-inserted intothe vagina. Exact positioning is not required for it to be effective.The vaginal ring must be inserted within 5 days of the onset of themenstrual period, even if bleeding is still occurring. During the firstcycle, an additional method of contraception is recommended. The ringremains in place continuously for three weeks. It is removed for oneweek. The next ring is then inserted one week after the last ring wasremoved. NON- CHLORAL HYDRATE The usual hypnotic dose is 500 mg to 1 g,taken 15 to 30 minutes BENZODIAZEPINE before bedtime or ½ hour beforesurgery. The usual sedative dose is ANXIOLYTICS 250 mg three times dailyafter meals. Generally, single doses or SEDATIVES daily dosage shouldnot exceed 2 g. HYPNOTICS CHLORAL BETAINE Chloral betaine 707 mg(chloral hydrate 414 mg) TRANQUILIZERS Dose: 1-2 tablets with water ormilk at bedtime, max. 5 tablets (2 g chloral hydrate) dailyCLOMETHIAZOLE (or MRTD (Maximum Recommended Therapeutic Dose) in mg/kg-CHLOMETHIAZOLE) body weight (bw)/day based upon an average adultweighing 60 kg - 6.40000 DIPHENHYDRAMINE Adults: 25 to 50 mg three orfour times daily. Children (over 20 lb): 12.5 to 25 mg three to fourtimes daily. Maximum daily dosage not to exceed 300 mg. ETHCHLORVYNOLDue to the problems it can cause, it is unusual for ethchlorvynol to beprescribed for periods exceeding seven days. PROMETHIAZINE.Administration of 12.5 to 25 mg Phenergan by the oral route or by rectalsuppository at bedtime will provide sedation in children. Adults usuallyrequire 25 to 50 mg for nighttime, presurgical, or obstetrical sedation.ZALPELON The recommended dose of Sonata for most nonelderly adults is 10mg. (imidazopyridine) For certain low weight individuals, 5 mg may be asufficient dose. Although the risk of certain adverse events associatedwith the use of Sonata appears to be dose dependent, the 20 mg dose hasbeen shown to be adequately tolerated and may be considered for theoccasional patient who does not benefit from a trial of a lower dose.ZOLPIDEM The recommended dose for adults is 10 mg immediately before(pyrazolopyrimidine) bedtime, indicated for the short-term treatment ofinsomnia. ZOPICLONE The usual dose is 7.5 mg at bedtime. This doseshould not be exceeded. Depending on clinical response and tolerance,the dose may be lowered to 3.75 mg. Geriatrics: In the elderly and/ordebilitated patient an initial dose of 3.75 mg at bedtime isrecommended. The dose may be increased to 7.5 mg if the starting dosedoes not offer adequate therapeutic effect. STIMULANTS CAFFEINE CaffeineOral is used to treat the following: Absence of Breathing in the NewbornCaffeine Oral may also be used to treat: Drowsiness, Low Energy Caffeinecitrate is indicated for the short term treatment of apnea ofprematurity in infants between 28 and <33 weeks gestational age.Caffeine Citrate: Loading Dose - 20 mg/kg Maintenance Dose - 5 mg/kgNICOTINE NICOTROL Inhaler is indicated as an aid to smoking cessationfor the relief of nicotine withdrawal symptoms. NICOTROL Inhaler therapyis recommended for use as proof of a comprehensive behavioral smokingcessation program. It it supplied as 42 cartridges each containing 10 mg(4 mg is delivered) nicotine. Initial Treatment: Up to 12 Weeks: 6-16cartridges/day Gradual Reduction (if needed) - 6-12 Weeks: No taperingstrategy has been shown to be superior to any other in clinical studies.OTC DEXTROMETHORPHAN Now prescription only in the United States.MEDICATIONS MRTD (Maximum Recommended Therapeutic Dose) in mg/kg- bodyweight (bw)/day based upon an average adult weighing 60 kg - 2.00000MISCELLANEOUS GHB It has been used as a general anesthetic, and ahypnotic in the Gamma-hydroxybutyrate treatment of insomnia. GHB hasalso been used to treat clinical depression, and improve athleticperformance. In the US, the FDA permits the use of GHB to reduce thenumber of cataplexy attacks in patients with narcolepsy. In Italy, GHBis used for the treatment of alcoholism (50 to 100 mg per kg per day, in3 or more divided doses), both for acute alcohol withdrawal and mediumto long term detoxification. LD50 of GHB is estimated to be between 1100mg/kg and 2000 mg/kg in rodents and is almost certainly lower in humans.MEPROBROMATE Meprobromate is available in 200 mg and 400 mg tablets fororal administration. Symptoms of meprobromate overdose include coma,drowsiness, loss of muscle control, severly impaired breathing, shock,sluggishness, and unresponsiveness. Death has been reported withingestion of as little as 12 g of meprobromate and survival with as muchas 40 g. METHQUALONE In the United States, the marketing of methaqualonepharmaceutical products stopped in 1984, and methaqualone wastransferred to Schedule I of the CSA. NITROUS OXIDE Nitrous Oxide is aweak general anesthetic, and is generally not used alone. It has a verylow short-term toxicity and is an excellent analgesic. In generalanesthesia it is often used in a 2:1 ratio with oxygen in addition tomore powerful general anesthetic agents. Possession of nitrous oxide isillegal in most localities in the United States for the purposes ofinhaling or ingesting if not under the care of a physician or dentist.PCP Not available for medicinal use. Phencyclidine HERBAL VALERIAN ROOTDosing not regulated/approved by FDA. MEDICINALS (Valeriana officinalis,Large doses are known to cause withdrawal symptoms when Valerianaceae)stopped, as it is mildly addictive. Those with liver disease are advisednot to use valerian. Valerian is the source of valeric acid. SALVINORINA N.A. Salvinorin A is the main active Salvinorin A is a dissociativehallucinogenic compound that is psychotropic constituent of the activeat the extremely low doses of 0.2-0.5 mg, second only to plant Salviadivinorum LSD in quantitative potency, making it the most potentnaturally (diviner's sage, Mexican mint). occurring drug known to date.A dose of 200 to 500 micrograms produces profound hallucinations whensmoked. Its' effects in the open field test in mice and loco motoractivity tests in rats are similar to mescaline. ST. JOHN'S WORT Thedosage of St John's wort preparations vary greatly between Refers to thespecies Hypericum formulations, due to variability in the plant sourceand preparation perforatum. processes. The doses of St. John's wortextract used in clinical trials generally range from 350 to 1800 mgdaily (equivalent to 0.4 to 2.7 mg hypericin depending on thepreparation). The recommended dosage for various forms of St John's wortas recommended by the British Herbal Medicine Association ScientificCommittee (1983) are as follows: dried herb: 2-4 g or by infusion threetimes daily liquid extract 2-4 mL (1:1 in 25% alcohol) three times dailytincture 2-4 mL (1:10 in 45% alcohol) three times daily ANTI- CITALOPRAMHBR Celexa (citalopram HBr) is indicated for the treatment of DEPRESSION(CELEXA) depression. DRUGS Celexa (citalopram HBr) should beadministered at an initial dose of 20 mg once daily, generally with anincrease to a dose of 40 mg/ day. Dose increases should usually occur inincrements of 20 mg at intervals of no less than one week ESCITALOPRAMOXALATE LEXAPRO (escitalopram) is indicated for the treatment of majorLEXAPRO ™ depressive disorder and Generalized Anxiety Disorder (GAD).The recommended dose of LEXAPRO is 10 mg once daily. FLUOXETINE Prozacis indicated for the treatment of: Major Depressive Disorder:HYDROCHLORIDE a dose of 20 mg/day, administered in the morning, isrecommended as the initial dose. The maximum fluoxetine dose should notexceed 80 mg/day. Obsessive Compulsive Disorder: a dose of 20 mg/day,administered in the morning, is recommended as the initial dose. Themaximum fluoxetine dose should not exceed 80 mg/day. Bulimia Nervosa:the recommended dose is 60 mg/day, administered in the morning. PanicDisorder: Treatment should be initiated with a dose of 10 mg/day. After1 week, the dose should be increased to 20 mg/day. PAROXETINE MajorDepressive Disorder: The recommended initial dose is HYDROCHLORIDE 20mg/day. Some patients not responding to a 20-mg dose may benefit fromdose increases, in 10-mg/day increments, up to a maximum of 50 mg/day.Obsessive Compulsive Disorder: The recommended dose of PAXIL in thetreatment of OCD is 40 mg daily. Patients should be started on 20 mg/dayand the dose can be increased in 10-mg/day increments. The maximumdosage should not exceed 60 mg/day. Panic Disorder: The target dose ofPAXIL in the treatment of panic disorder is 40 mg/day. The maximumdosage should not exceed 60 mg/day. Social Anxiety Disorder: Therecommended and initial dosage is 20 mg/day. Generalized AnxietyDisorder: The recommended starting dosage and the established effectivedosage is 20 mg/day. Posttraumatic Stress Disorder: The recommendedstarting dosage and the established effective dosage is 20 mg/day.FLUVOXAMINE MALEATE Fluvoxamine is indicated in the treatment ofdepression and for (LUVOX). Obsessive Compulsive Disorder (OCD). Therecommended starting dose for LUVOX Tablets in adult patients is 50 mg,administered as a single daily dose at bed time. The maximum therapeuticdose should not to exceed 300 mg per day. SERTRALINE Major DepressiveDisorder and Obsessive-Compulsive Disorder: HYDROCHLORIDE ZOLOFTtreatment should be administered at a dose of 50 mg once daily. PanicDisorder, Posttraumatic Stress Disorder and Social Anxiety Disorder:ZOLOFT treatment should be initiated with a dose of 25 mg once daily.After one week, the dose should be increased to 50 mg once daily.Premenstrual Dysphoric Disorder: ZOLOFT treatment should be initiatedwith a dose of 50 mg/day, either daily throughout the menstrual cycle orlimited to the luteal phase of the menstrual cycle, depending onphysician assessment. AMITRIPTYLINE For the relief of symptoms ofdepression. Endogenous depression is more likely to be alleviated thanare other depressive states. Oral Dosage: 75 mg of amitriptyline HCl aday in divided doses. If necessary, this may be increased to a total of150 mg per day. Intramuscular Dosage: Initially, 20 to 30 mg (2 to 3 ml)four times a day. DESIPRAMINE Desipramine hydrochloride is indicated forrelief of symptoms in HYDROCHLORIDE various depressive syndromes,especially endogenous depression. The usual adult dose is 100 to 200 mgper day. Dosages above 300 mg/day are not recommended. Not recommendedfor use in children. NORTRIPTYLINE Nortriptyline HCl is indicated forthe relief of symptoms of depression. Endogenous depressions are morelikely to be alleviated than are other depressive states. It is notrecommended for children. Usual Adult Dose - 25 mg three or four timesdaily. Doses above 150 mg/day are not recommended. Elderly andAdolescent Patients - 30 to 50 mg/day, in divided doses, or the totaldaily dosage may be given once a day. DULOXETINE Cymbalta is indicatedfor the treatment of major depressive disorder HYDROCHLORIDE (MDD) andpain associated with diabetic peripheral neuropathy. Major DepressiveDisorder: Cymbalta should be administered at a total dose of 40 mg/dayDiabetic Peripheral Neuropathic Pain: Cymbalta should be administered ata total dose of 60 mg/day given once a day VENLAFAXINE Effexor(venlafaxine hydrochloride) is indicated for the treatment of Effexormajor depressive disorder. The recommended starting dose for Effexor is75 mg/day, up to a maximum of 375 mg/day, generally in three divideddoses PHENELZINE SULFATE The usual starting dose of Nardil is one tablet(15 mg) three times a day. Maintenance dose may be as low as one tablet,15 mg, a day or every other day, and should be continued for as long asis required. TRANYLCYPROMINE For the treatment of Major DepressiveEpisode Without (Parnate) Melancholia. The usual effective dosage is 30mg per day, usually given in divided doses; may be extended to a maximumof 60 mg per day. When tranylcypromine is withdrawn, monoamine oxidaseactivity is recovered in 3 to 5 days, although the drug is excreted in24 hours. MIRTAZEPINE Indicated for the treatment of major depressivedisorder. The recommended starting dose for REMERON ® (mirtazapine)Tablets is 15 mg/day, up to a maximum of 45 mg/day. NEFAZODONE SERZONE(nefazodone hydrochloride) is indicated for the HYDROCHLORIDE treatmentof depression. When deciding among the alternative SERZONE ® treatmentsavailable for this condition, the prescriber should consider the risk ofhepatic failure associated with SERZONE treatment. The recommendedstarting dose for SERZONE (nefazodone hydrochloride) is 200 mg/dayTRAZODONE DESYREL is indicated for the treatment of depression.HYDROCHLORIDE An initial dose of 150 mg/day in divided doses issuggested, up to DESYREL but not in excess of 600 mg/day in divideddoses. BUPROPION WELLBUTRIN is indicated for the treatment ofdepression. HYDROCHLORIDE The usual adult dose is 300 mg/day, given 3times daily. WELLBUTRIN (bupropion WELLBUTRIN should be discontinued inpatients who do not hydrochloride) demonstrate an adequate responseafter an appropriate period of treatment at 450 mg/day. When Wellbutrinis used in combination with an SSRI to offset sexual side effects, theusual dose is 75 mg per day. Isocarboxazid The maximum daily dose ofisocarboxazid is 60 mg. Moclobemide Depression: The initial dose is 300mg daily in 2 or 3 divided doses. Social Phobia: The recommended dose is600 mg daily in 2 or 3 divided doses. A single 300 mg dose ofmoclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% ofmonoamine oxidase B (MAO-B), blocking the decomposition ofnorepinephrine, serotonin and, to a lesser extent, dopamine. No reuptakeinhibition on any of the neurotransmitters occurs. Selegiline 10 mg perday administered as divided doses of 5 mg each. NEUROSTEROID 5-ALPHA-INHIBITORS REDUCTASE INHIBITORS FINASTERIDE The recommended dosage is 1mg orally once per day. It may be administered with or without meals. Analternate dosage of 5 mg orally once per day is also included. It may beadministered with or without meals. In general, daily use for threemonths or more is necessary before benefit is observed. Continued use isrecommended to sustain benefit, which should be re-evaluatedperiodically. Withdrawal of treatment leads to reversal of effect within12 months. In clinical studies, single doses of finasteride up to 400 mgand multiple doses of finasteride up to 80 mg/day for three months didnot result in adverse reactions. DUTASTERIDE The recommended therapeuticdose of dutasteride is 0.5 mg taken orally once per day. Dutasteridepharmacokinetics has not been investigated in subjects less than 18years of age. No dose adjustment is necessary in the elderly. Involunteer studies, single doses of dutasteride up to 40 mg (80 times thetherapeutic dose) for 7 days have been administered without significantsafety concerns. In a clinical study, daily doses of 5 mg (10 times thetherapeutic dose) were administered to 60 subjects for 6 months with noadditional adverse effects to those seen at therapeutic does of 0.5 mg.SAW PALMETTO Tablets/Capsules. A dose of 160 mg twice daily or 320milligrams daily (containing 80% to 90% liposterolic content) for up to11 months has been taken by mouth. Higher doses may be used undermedical supervision. Berries. A dose of one to two grams of ground,dried, or whole berries daily has been taken by mouth. Tincture. A doseof two to four milliliters (1:4) three times daily has been taken bymouth. Fluid Extract of Berry Pulp. A dose of one to two milliliters(1:1) three times daily has been taken by mouth. Rectal Suppositories. Adose of 640 milligrams once daily has been used. Rectal use of sawpalmetto is no better than taking saw palmetto by mouth. Tea. Tea madefrom berries may not be effective because the proposed active ingredientdoes not dissolve in water. SPIRONOLACTONE Treatment protocols mayinvolve continuous spironolactone use at 50 mg to 200 mg per day orcyclic use; for example, 50 mg or 100 mg twice daily from the 4^(th) tothe 22^(nd) day of the menstrual cycle. Numerous treatment protocolsinvolving spironolactone have been used in different studies, but noparticular treatment approach has been shown to be significantlysuperior. 3-ALPHA REDUCTASE INHIBITORS INDOMETHACIN Indomethacin can beadministered in the form of capsules (25 mg and 50 mg);sustained-release capsules (75 mg); a suspension (25 mg/ml); or asuppository (50 mg). The recommended dose for adults is 50-200 mg perday split into 2-3 doses. CLASS OF FLUMAZENIL ROMAZICON is indicated forthe complete or partial reversal of COMPOUNDS (Romazicon) the sedativeeffects of benzodiazepines in cases where general THAT anesthesia hasbeen induced and/or maintained with SELECTIVELY benzodiazepines, wheresedation has been produced with MODULATES benzodiazepines for diagnosticand therapeutic procedures, and for GABA_(A) the management ofbenzodiazepine overdose. Reversal of RECEPTORS Conscious Sedation: Therecommended initial dose of ROMAZICON is 0.2 mg (2 mL) administeredintravenously over 15 seconds. If the desired level of consciousness isnot obtained after waiting an additional 45 seconds, a second dose of0.2 mg (2 mL) can be injected and repeated at 60-second intervals wherenecessary (up to a maximum of 4 additional times) to a maximum totaldose of 1 mg (10 mL). Reversal of General Anesthesia in Adult Patients:The recommended initial dose of ROMAZICON is 0.2 mg (2 mL) administeredintravenously over 15 seconds. If the desired level of consciousness isnot obtained after waiting an additional 45 seconds, a further dose of0.2 mg (2 mL) can be injected and repeated at 60-second intervals wherenecessary (up to a maximum of 4 additional times) to a maximum totaldose of 1 mg (10 mL). Management of Suspected Benzodiazepine Overdose inAdult Patients: the recommended initial dose of ROMAZICON is 0.2 mg (2mL) administered intravenously over 30 seconds. If the desired level ofconsciousness is not obtained after waiting 30 seconds, a further doseof 0.3 mg (3 mL) can be administered over another 30 seconds. Furtherdoses of 0.5 mg (5 mL) can be administered over 30 seconds at 1-minuteintervals up to a cumulative dose of 3 mg. MILTIRONE The below doses arebased on scientific research, publications, traditional use, or expertopinion. Many herbs and supplements have not been thoroughly tested, andsafety and effectiveness may not be proven. You should read productlabels, and discuss doses with a qualified healthcare provider beforestarting therapy. Standardization: There is no widely acceptedstandardization or well-studied dosing of miltirone, and many differentdoses are used traditionally. Adults (18 years and older): By mouth:Oral dosing has not been studied in well-conducted trials in humans, andtherefore no specific dose can be recommended. By injection: In researchfrom the 1970s, an 8 milliliter injection of miltirone (16 grams of theherb) was given intravenously (diluted in 500 milliliters of a 10%glucose solution) for up to four weeks for ischemic stroke. Safety andeffectiveness have not been established for this route of administrationand it cannot not recommended at his time. Children (younger than 18years): There is not enough scientific evidence to recommend the safeuse of danshen in children, and it should be avoided due to potentiallyserious side effects. FLAVONOIDS They have been classified N.A.according to their chemical structure, and are usually subdivided into 6subgroups: Flavonols, including Quercetin, Kaempferol, Myricetin,Isorhamnetin Flavones, including Luteolin, Apigenin Flavanones,including Hesperetin, Naringenin, Eriodictyol Flavan-3-ols, including(+)- Catechin, (+)-Gallocatechin, (−)- Epicatechin, (−)-*Epigallocatechin, (−)- Epicatechin 3-gallate, (−)- Epigallocatechin3-gallate, Theaflavin, Theaflavin 3- gallate, Theaflavin 3′-gallate,Theaflavin 3,3′ digallate, Thearubigins Isoflavones, includingGenistein, Daidzein, Glycitein Anthocyanidins, including Cyanidin,Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin DOPAMINE ERGOTThe dose of bromocriptine will be different for different patients.change your dose over several weeks as needed. Teenagers less than 15years of age and children-Use and dose must be determined by yourdoctor. For pituitary tumors: Adults and teenagers 15 years of age orolder-At first, 1.25 milligrams (mg) two or three times a day taken withmeals. Then your doctor may change your dose over several weeks asneeded. Teenagers less than 15 years of age and children-Use and dosemust be determined by your doctor. PRESCRIPTION METHYLPHENIDATEMethylphendiate comes in 5 mg, 10 mg and 20 mg tablets. STIMULANTSADULTS Tablets: Administer in divided doses, 2 or 3 times daily,preferably 30 to 45 minutes before meals. Average dosage is 20 to 30 mgdaily. Some patient may require 40 to 60 mg daily. In others, 10 to 15mg daily will be adequate. FOR CHILDREN, DOSAGES SHOULD BE INITIATED ININCREMENTS Days 1-3: One 5 mg tablet per day Days 4-6: Two 5 mg tabletsper day Add one pill every fourth day until a dosage of 20 mg per day isachieved. Daily dosage above 60 mg is not recommended. ADDERALL.Attention Deficit Disorder with Hyperactivity: Not recommended forchildren under 3 years of age. In children from 3 to 5 years of age,start with 2.5 mg daily; daily dosage may be raised in increments of 2.5mg at weekly intervals until optimal response is obtained. In children 6years of age and older, start with 5 mg once or twice daily; dailydosage may be raised in increments of 5 mg at weekly intervals untiloptimal response is obtained. Only in rare cases will it be necessary toexceed a total of 40 mg per day. Give first dose on awakening;additional doses (1 or 2) at intervals of 4 to 6 hours. Where possible,drug administration should be interrupted occasionally to determine ifthere is a recurrence of behavioral symptoms sufficient to requirecontinued therapy. Narcolepsy: Usual dose 5 mg to 60 mg per day individed doses, depending on the individual patient response. Narcolepsyseldom occurs in children under 12 years of age; however, when it does,dextroamphetamine sulfate may be used. The suggested initial dose forpatients aged 6-12 is 5 mg daily; daily dose may be raised in incrementsof 5 mg at weekly intervals until optimal response is obtained. Inpatients 12 years of age and older, start with 10 mg daily; daily dosagemay be raised in increments of 10 mg at weekly intervals until optimalresponse is obtained. If bothersome adverse reactions appear (e.g.,insomnia or anorexia), dosage should be reduced. Give first dose onawakening; additional doses (1 or 2) at intervals of 4 to 6 hours.DEXEDRINE Narcolepsy. Usual dose 5 to 60 mg per day in divided doses,depending on the individual patient response. Narcolepsy seldom occursin children under 12 years of age; however, when it does Dexedrine(dextroamphetamine sulfate) may be used. The suggested initial dose forpatients aged 6 to 12 is 5 mg daily; daily dose may be raised inincrements of 5 mg at weekly intervals until optimal response isobtained. In patients 12 years of age and older, start with 10 mg daily;daily dosage may be raised in increments of 10 mg at weekly intervalsuntil optimal response is obtained. If bothersome adverse reactionsappear (e.g. insomnia or anorexia), dosage should be reduced. Spansulecapsules may be used for once-a-day dosage wherever appropriate. Withtablets give first dose on awakening, additional doses (1 or 2) atintervals of 4 to 6 hours. AGONISTS ALKALOIDS Follow your doctor'sorders or the directions on the label. The following informationincludes only the average doses of bromocriptine. If your dose isdifferent, do not change it unless your doctor tells you to do so. Thenumber of capsules or tablets that you take depends on the strength ofthe medicine. Also, the number of doses you take each day, the timeallowed between doses, and the length of time you take the medicinedepend on the medical problem for which you are taking bromocriptine.For oral dosage forms (capsules and tablets): For infertility, malehormone problem (male hypogonadism), starting the menstrual cycle(amenorrhea), or stopping abnormal milk secretion from nipples(galactorrhea): Adults and teenagers 15 years of age or older-At first,1.25 to 2.5 milligrams (mg) once a day taken at bedtime with a snack.Then your doctor may change your dose by 2.5 mg every three to sevendays as needed. Doses greater than 5 mg a day are taken in divided doseswith meals or at bedtime with a snack. Teenagers less than 15 years ofage and children-Use and dose must be determined by your doctor. Forlowering growth hormone (acromegaly): Adults and teenagers 15 years ofage or older-At first, 1.25 to 2.5 milligrams (mg) once a day taken atbedtime with a snack for three days. Then your doctor may change yourdose by 1.25 or 2.5 mg every three to seven days as needed. Dosesgreater than 5 mg are divided into smaller doses and taken with meals orat bedtime with a snack. Teenagers less than 15 years of age andchildren-Use and dose must be determined by your doctor. For Parkinson'sdisease: Adults and teenagers 15 years of age or older-At first, 1.25milligrams (mg) one or two times a day taken with meals or at bedtimewith a snack. Then your doctor may Attention Deficit Disorder withHyperactivity. Not recommended for pediatric patients under 3 years ofage. In pediatric patients from 3 to 5 years of age, start with 2.5 mgdaily, by tablet daily dosage may be raised in increments of 2.5 mg atweekly intervals until optimal response is obtained. In pediatricpatients 6 years of age and older, start with 5 mg once or twice daily,daily dosage may be raised in increments of 5 mg at weekly intervalsuntil optimal response is obtained. Only in rare cases will it benecessary to exceed a total of 40 mg per day. Spansule capsules may beused for once-a-day dosage wherever appropriate. With tablets, givefirst dose on awakening additional doses (1 or 2) at intervals of 4 to 6hours.

1-26. (canceled)
 27. A method of treating addiction to anti-depressants,opiates, nicotine or marijuana in a patient comprising administering tothe patient a composition comprising a compound that selectivelymodulates GABA_(A) receptor expression and a pharmaceutically acceptablecarrier.
 28. The method of claim 27, wherein the compound is flumazenilor miltirone.
 29. The method of claim 28, wherein the flumazenil isadministered in a therapeutically effective quantity.
 30. The method ofclaim 29, wherein the therapeutically effective quantity of flumazenilis between 0.5 mg/day and 10 mg/day.
 31. The method of claim 28, whereinthe flumazenil is administered at a rate of between 0.1 and 0.3 mg overpredetermined time intervals for a total administration of between 0.5mg/day and 10 mg/day.
 32. The method of claim 31, wherein thepredetermined time interval is in the range of 1 and 15 minutes.
 33. Themethod of claim 28, wherein the flumazenil is administered at a rate ofbetween 0.1 and 0.3 mg over predetermined time intervals for a totaladministration of between 1.0 mg/day and 3.0 mg/day.
 34. The method ofclaim 27, further comprising administering an inhibitor of neurosteroidproduction in a pharmaceutically acceptable carrier prior toadministering the composition comprising the compound that selectivelymodulates GABA_(A) receptor expression.
 35. The method of claim 34,wherein the inhibitor of neurosteroid production is a 5-alpha-reductaseinhibitor.
 36. The method of claim 35, wherein the 5-alpha-reductaseinhibitor is finasteride.
 37. The method of claim 36, wherein thefinasteride is administered in an amount of less than 10 mg/day.
 38. Amethod of treating addiction to anti-depressants, opiates, nicotine ormarijuana in a patient comprising: assessing the patient for treatmentcompatibility; preparing the patient for treatment; and, administeringto the patient a composition comprising a compound that selectivelymodulates GABA_(A) receptor expression in a pharmaceutically acceptablecarrier.
 39. The method of claim 38, wherein preparing the patient fortreatment includes withdrawing the patient from current treatment. 40.The method of claim 38, wherein preparing the patient for treatmentincludes placing the patient in a state of withdrawal.
 41. The method ofclaim 40, wherein the patient is a female patient and the female patientis placed in a state of withdrawal by administering to the femalepatient a contraceptive and then ceasing administration of thecontraceptive.
 42. The method of claim 40, wherein the patient is placedin a state of withdrawal by administering to the patient a compositioncomprising an inhibitor of neurosteroid production in a pharmaceuticallyacceptable carrier.
 43. The method of claim 38, wherein the compound isflumazenil.
 44. The method of claim 43, wherein the flumazenil isadministered in a therapeutically effective quantity.
 45. The method ofclaim 44, wherein the therapeutically effective quantity of flumazenilis between 0.5 mg/day and 10 mg/day.
 46. The method of claim 43, whereinthe flumazenil is administered at a rate of between 0.1 and 0.3 mg overpredetermined time intervals for a total administration of between 0.5mg/day and 10 mg/day.
 47. The method of claim 46, wherein thepredetermined time interval is in the range of 1 and 15 minutes.
 48. Themethod of claim 43, wherein the flumazenil is administered at a rate ofbetween 0.1 and 0.3 mg over predetermined time intervals for a totaladministration of between 1.0 mg/day and 3.0 mg/day.
 49. The method ofclaim 42, wherein the inhibitor of neurosteroid production is a5-alpha-reductase inhibitor.
 50. The method of claim 49, wherein the5-alpha-reductase inhibitor is finasteride.
 51. The method of claim 50,wherein the finasteride is administered in an amount of less than 10mg/day.